3D Bioprinted Liver Tissue Constructs Used to Develop More Accurate Drug Toxicity Testing System

While many think that bioprinting means that we’ll soon be able to 3D print a brand new organ with the touch of a button, that’s not the case quite yet. However, there have been several recent bioprinting advancements that show the technology has definite applications in terms of drug testing. Drug screen applications require a great deal of precision, which means that any biomimetic constructs made for testing purposes have to accurately mimic the behaviors and characteristics of tissues in terms of drug absorption. An international research collaboration created a simple liver model, with 3D bioprinted tissue, in order to develop a more accurate drug toxicity testing system. The research team’s new 3D bioprinted liver tissue constructs make it possible for these tests to be even more highly accurate.

According to this innovative research, the researchers’ new advancement can construct vascularized tissue, which is then able to mimic drug administration in vivo in 3D bioprinted liver tissue. Typically, two-dimensional cell models are used for these types of tests, but the research team’s 3D structure is better able to replicate human tissue’s complex architecture, due to its improved cellular functions and cell-to-cell interactions; therefore, it can also provide more realistic responses to drugs and the body’s toxicity levels.

Su Ryon Shin, an instructor who’s working on this research at Harvard Medical School, said, “Most drug test models use a two-dimensional (2-D) monolayer cell tissue, or a 3-D tissue, but without this network. Our bodies are actually composed of a 3-D construct with a vascular network, not composed of [just] single cells.”

The work was recently published in a paper titled “Bioprinted 3D vascularized tissue model for drug toxicity analysis,” in Biomicrofluidics. Along with Harvard, institutions around the world participated in the study: KTH Royal Institute of Technology in Sweden, Universidad de los Andes in Colombia, IRCCS Istituto Ortopedico Galeazzi in Italy, Konkuk University in South Korea, and King Abdulaziz University in Saudi Arabia.

The paper’s abstract reads, “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.”

The endothelial cell-layered channel network was 3D printed with bioink that makes use of sacrificial microchannel scaffolding.

Shin said, “We are using human cells, and when we developed this technique we [did so in a way that let us] easily change the cell type, using maybe a patient’s primary cell or their endothelial cells and we can [potentially] create a human-specialized tissue model.”

The research team’s creation is extremely helpful, as it allows scientists to observe the in vivo effects of drug absorption without having to actually set up a real in vivo study. The vascular model is not perfect: it’s still a much simpler version of human liver tissue, but it has achieved a “new level of complexity,” which the team took advantage of in order to make an important discovery that would not have been possible with a 2D monolayer construct.

“Based on our finding, the endothelial layer delays the drug diffusion response, compared to without the endothelial layer. They don’t change any drug diffusion constants, but they delay the permeability, so they delay the [response] as it takes time to pass through the endothelial layer,” Shin explained.

In the future, the team’s technique could also be adapted to different cell types and used to offer drug toxicity testing that’s patient-specific. The researchers hope that their work will help others develop faster, even more complex bioprinted drug testing systems, like multi-organ-on-a-chip devices, while Shin plans to focus more on the drug diffusion finding, and how to tune it in order to optimize drug absorption.

Study authors include Solange Massa, Mahmoud Ahmed Sakr, Jungmok Seo, Praveen Bandaru, Andrea Arneri, Simone Bersini, Elaheh Zare-Eelanjegh, Elmira Jalilian, Byung-Hyun Cha, Silvia Antona, Alessandro Enrico, Yuan Gao, Shabir Hassan, Juan Pablo Acevedo, Mehmet R. Dokmeci, Yu Shrike Zhang, Ali Khademhosseini, and Su Ryon Shin.

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