Microbioreactors for high-throughput cytotoxicity assays

Abstract

Cell culture plays a fundamental role in the biotechnology and pharmaceutical industries, impacting both drug discovery and manufacturing as well as regenerative medicine. In drug discovery, cell-based assays are increasingly being used for drug target validation and drug ADMET (absorption, distribution, metabolism, elimination and toxicity) studies because cells can provide more representative responses to drugs than simple molecular assays and are easier to use in a high-throughput format than animals. There are, however, intrinsic drawbacks associated with conventional in vitro cellular tests using two-dimensional cultures, in that they lack a three-dimensional (3D) scaffold to support cell growth and proper tissue function, and cannot mimic in vivo cellular conditions. Tailoring scaffold properties for 3D cell cultures is therefore essential in developing a representative in vitro tissue model for cytotoxicity assays. Recently, microfluidic bioreactors with miniaturized culturing vessels and high controllability for operation and on-line monitoring/sensing have gained popularity in bioprocess development and cell-based assays. The advancement in this field has been enabled by the development of novel cell lines and reporter gene techniques, as well as new microfabrication, microfluidics and optical and electrochemical sensor technologies. Non-invasive detection methods using reporter genes and label-free techniques allow for real-time dynamic monitoring of viable cell number and cellular activities. Microbioreactors with continuous perfusion allow for long-term culturing to study chronic toxicity effects. Systemic toxicity and interactions between different cell types can also be studied on a biochip. High-density microfluidic arrays provide a platform for future high-throughput and high-content screening that will contribute to drug discovery and bioprocess development.