Direct Microextrusion Printing of a Low Viscosity Hydrogel on a Supportive Microstructured Bioprinting Substrate for the Vasculogenesis of Endothelial Cells

Natural hydrogels with low viscosity and high cytocompatibility are limited in their application as bioinks because their poor mechanical properties lead to constructs of low resolution that fail to reflect the high spatial control of the bioprinter. Existing attempts to integrate natural hydrogels with low viscosity into bioprinting compromise bioink cytocompatibility for printability and complicate the printing and crosslinking process. Consequently, biological phenomena such as vasculogenesis, which require high levels of cellular bioactivities including cell adhesion, proliferation, and migration, are difficult to observe in high‐resolution bioprinted constructs. This study proposes a novel technique of bioprinting on a supportive microstructured bioprinting substrate (SuBstrate) to enhance the structural fidelity of low‐viscosity hydrogel constructs via capillary pinning and to maintain their integrity during the crosslinking procedures. This bioprinting approach enables the direct and reproducible microextrusion printing of fibrinogen, a hydrogel previously considered “unprintable” using such a method, into volumetric constructs that are vascularized by the self‐assembly of endothelial cells, replicating the biological vasculogenesis process. The SuBstrate‐based bioprinting technology can be applied to bioprinting cytocompatible natural hydrogels to develop complex constructs and is expected to be used as a new method of recreating physiological tissues for pathological studies and drug screening. A novel supportive microstructured bioprinting substrate (SuBstrate) is developed for the direct microextrusion bioprinting of a low‐viscosity natural hydrogel with high structural fidelity and reproducibility. The SuBstrate enables high‐resolution bioprinting of fibrin without compromising cytocompatibility via capillary pinning and is applied to fabricate complex volumetric constructs in which endothelial cells could spontaneously organize to form permeable vasculatures.