Advanced 3D Cell Culture Techniques in Micro-Bioreactors, Part I: A Systematic Analysis of the Literature Published between 2000 and 2020

Christoph Grün,Eric Gottwald,Brigitte Altmann

doi:10.3390/pr8121656

Christoph Grün, Eric Gottwald + Show 1 more

Open Access

https://doi.org/10.3390/pr8121656

Copy DOI

Abstract

Bioreactors have proven useful for a vast amount of applications. Besides classical large-scale bioreactors and fermenters for prokaryotic and eukaryotic organisms, micro-bioreactors, as specialized bioreactor systems, have become an invaluable tool for mammalian 3D cell cultures. In this systematic review we analyze the literature in the field of eukaryotic 3D cell culture in micro-bioreactors within the last 20 years. For this, we define complexity levels with regard to the cellular 3D microenvironment concerning cell–matrix-contact, cell–cell-contact and the number of different cell types present at the same time. Moreover, we examine the data with regard to the micro-bioreactor design including mode of cell stimulation/nutrient supply and materials used for the micro-bioreactors, the corresponding 3D cell culture techniques and the related cellular microenvironment, the cell types and in vitro models used. As a data source we used the National Library of Medicine and analyzed the studies published from 2000 to 2020.

Highlights

Micro-bioreactors (MBRs) represent specialized bioreactor systems that were, unlike their big brothers, namely classical bioreactors for biotechnological applications or industrial production, developed for growing mammalian cells and/or tissues in vitro on a smaller scale
2014, with microfluidic MBRs being most strongly represented in the fields of fundamental research with in vitro models, tissue engineering, and HTS
With respect to the cell culture configuration used in the MBR systems during this period, 3D aggregates of the same cell type, consisting mainly of human primary cells or cell lines are the most frequently used technique in this period, irrespective

Summary

Introduction

Micro-bioreactors (MBRs) represent specialized bioreactor systems that were, unlike their big brothers, namely classical bioreactors for biotechnological applications or industrial production, developed for growing mammalian cells and/or tissues in vitro on a smaller scale. (ii) spatial distribution of cell–extracellular matrix (ECM) interactions, which are inevitably coupled with the molecular and mechanical ECM properties, (iii) the spatial distribution of homologous and heterologous cell–cell contacts, and (iv) biomechanical forces emerging from interstitial fluid flow and tissue deformation Against this background and within the scope of this special issue of Processes bearing the same title, we would like to give an overview of the work published in the last 20 years in the area of 3D cell culture in micro-bioreactors and to thereby address the following questions:. To answer these questions, we reviewed the studies in the field of 3D cell culture in MBRs between the years 2000 and 2020 (9 July 2020) systematically with respect to MBR design, the corresponding 3D cell culture techniques and the related cellular microenvironment, the mode of cell stimulation and/or nutrient supply, the materials used for MBRs and scaffold fabrication, the applications of the systems and the used cell type or in vitro model. We hope to be able to adequately introduce the reader into the great contributions of this special issue of Processes on Advanced 3D-Cell Culture Techniques in Micro-Bioreactors

Methods and Definitions

Findings

Conclusions