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 in vivo. 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 in vitro liver model system for future drug toxicity testing.
Bibliographical noteFunding Information:
The authors gratefully acknowledge funding from the Defense Threat Reduction Agency (DTRA) under Space and Naval Warfare Systems Center Pacific (SSC PACIFIC) Contract No. N66001-13-C-2027. The publication of this material does not constitute approval by the government of the findings or conclusions herein. The authors also acknowledge funding from the Institute for Soldier Nanotechnology, National Institutes of Health (HL092836, EB012597, AR057837, and HL099073), and the Office of Naval Research PECASE Award. Solange Massa is thankful for the support received by Universidad de los Andes (Chile) and Programa de Mejoramiento Institucional (PMI). Su Ryon Shin would like to recognize and thank Brigham and Women's Hospital President Betsy Nabel, MD, and the Reny family, for the Stepping Strong Innovator Award through their generous funding. Dr. Seo was partially supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2016R1A6A3A03006491). Andrea Arneri acknowledges the funding from the Italian Ministry of Health. Yu Shrike Zhang acknowledges the National Institutes of Health National Cancer Institute Pathway to Independence Award (K99CA201603). The authors declare no conflict of interest.