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Genes (Basel). 2018 Mar 22;9(4). pii: E176. doi: 10.3390/genes9040176.

Bioprinting Perfusion-Enabled Liver Equivalents for Advanced Organ-on-a-Chip Applications.

Author information

1
Cellbricks GmbH, 13355 Berlin, Germany. tg@cellbricks.com.
2
Fachgebiet für Medizinische Biotechnologie, Technische Universität Berlin, 13355 Berlin, Germany. alicia.ruppelt@gmail.com.
3
Cellbricks GmbH, 13355 Berlin, Germany. at@cellbricks.com.
4
Fachgebiet für Medizinische Biotechnologie, Technische Universität Berlin, 13355 Berlin, Germany. aka@cellbricks.com.
5
Fachgebiet für Medizinische Biotechnologie, Technische Universität Berlin, 13355 Berlin, Germany. bn@cellbricks.com.
6
Fachgebiet für Medizinische Biotechnologie, Technische Universität Berlin, 13355 Berlin, Germany. roland.lauster@tu-berlin.de.
7
Cellbricks GmbH, 13355 Berlin, Germany. lk@cellbricks.com.

Abstract

Many tissue models have been developed to mimic liver-specific functions for metabolic and toxin conversion in in vitro assays. Most models represent a 2D environment rather than a complex 3D structure similar to native tissue. To overcome this issue, spheroid cultures have become the gold standard in tissue engineering. Unfortunately, spheroids are limited in size due to diffusion barriers in their dense structures, limiting nutrient and oxygen supply. Recent developments in bioprinting techniques have enabled us to engineer complex 3D structures with perfusion-enabled channel systems to ensure nutritional supply within larger, densely-populated tissue models. In this study, we present a proof-of-concept for the feasibility of bioprinting a liver organoid by combining HepaRG and human stellate cells in a stereolithographic printing approach, and show basic characterization under static cultivation conditions. Using standard tissue engineering analytics, such as immunohistology and qPCR, we found higher albumin and cytochrome P450 3A4 (CYP3A4) expression in bioprinted liver tissues compared to monolayer controls over a two-week cultivation period. In addition, the expression of tight junctions, liver-specific bile transporter multidrug resistance-associated protein 2 (MRP2), and overall metabolism (glucose, lactate, lactate dehydrogenase (LDH)) were found to be stable. Furthermore, we provide evidence for the perfusability of the organoids' intrinsic channel system. These results motivate new approaches and further development in liver tissue engineering for advanced organ-on-a-chip applications and pharmaceutical developments.

KEYWORDS:

3D cell-culture; bioink; bioprinting; drug development; in vitro testing; liver equivalent; stereolithography; tissue engineering; toxin testing

Conflict of interest statement

The authors declare no conflicts of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

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