Bioprinted 3D vascularized tissue model for drug toxicity analysis

Abstract

To develop biomimetic three-dimensional (3D) tissue constructs for drug screening and biological studies, engineered blood vessels should be integrated into the constructs to mimic the drug administration process . The development of perfusable vascularized 3D tissue constructs for studying the drug administration process through an engineered endothelial layer remains an area of intensive research. Here, we report the development of a simple 3D vascularized liver tissue model to study drug toxicity through the incorporation of an engineered endothelial layer. Using a sacrificial bioprinting technique, a hollow microchannel was successfully fabricated in the 3D liver tissue construct created with HepG2/C3A cells encapsulated in a gelatin methacryloyl hydrogel. After seeding human umbilical vein endothelial cells (HUVECs) into the microchannel, we obtained a vascularized tissue construct containing a uniformly coated HUVEC layer within the hollow microchannel. The inclusion of the HUVEC layer into the scaffold resulted in delayed permeability of biomolecules into the 3D liver construct. In addition, the vascularized construct containing the HUVEC layer showed an increased viability of the HepG2/C3A cells within the 3D scaffold compared to that of the 3D liver constructs without the HUVEC layer, demonstrating a protective role of the introduced endothelial cell layer. The 3D vascularized liver model presented in this study is anticipated to provide a better and more accurate liver model system for future drug toxicity testing.

Liver‐on‐a‐Chip Models of Fatty Liver Disease

“…However, they are typically static and limited in architecture and incorporation of multiple cell types. To improve this, researchers developed 3D, dynamic models using human cells in combination with microfluidic, microphysiological platforms, referred to as “liver‐on‐a‐chip” models …”

Biotechnology Challenges to In Vitro Maturation of Hepatic Stem Cells

“…137–141 These novel techniques allow for the precise and simultaneous addition of cells and matrix molecules in a designed spatial configuration. With proper spatial control, bioprinters generate hepatic tissues with distinct cell types in discrete locations that resemble hepatic tissue architecture and cell distribution.…”

“…138 These bioprinted, often called mini-livers, have some features of hepatocyte function, including albumin and urea secretion and drug metabolism to a certain level. 138,140,141 However, the low resolution of available bioprinters and methods for bioprinting the vasculature (such as sacrificial hydrogel) make it impossible to print hepatic tissue with an integrated and perfusable vascular network with complex branching in a range of diameters from large vessels to capillaries. 142,143 The same holds true for the periportal to pericentral zonal distrubition.…”

Innovation for hepatotoxicity in vitro research models: A review

“…Stem cells can be better differentiated into HLCs in 3D liver bioprinting. It is gentle enough to print iPSCs, while maintaining their pluripotency or directing their differentiation into specific lineages (Faulkner‐Jones et al, ; Massa et al, ). Ma et al used digital‐light‐processing‐based 3D printing for fabrication of complex 3D microstructures.…”