High throughput physiological micro-models for in vitro pre-clinical drug testing: a review of engineering systems approaches

To address the low success rate of new drug discovery, there has been significant growth of in vitro physiological micro-models based on human cells. These may be in the form of cell spheroids, organs-on-a-chip, or multi-cellular tissue cultures, and it is expected that the more biomimetic environment they create will be more accurate than standard cell culture in drug screening prior to clinical testing. However, commercial use of complex co-cultures is still limited. This is due to a lack of validation, low throughput rates, and a lack of compatibility with standard assessment techniques. This review paper focusses specifically on the different engineering approaches used to create, mature and analyse these micro-models, with the aim of exploring which approaches have the potential for high throughput. Active and passive pumping and nozzle based dispensing techniques are considered for fluid handling, with transwells, cell patterning, spheroid cultures and microfluidics considered for establishing and maintaining co-cultures, together with conventional analysis techniques (proteomic and genomic approaches, and immunohistochemistry) and novel sensor systems for downstream analysis are considered. It is concluded that (i) throughput is essential for validation as well as exploitation of the models, and (ii) an integrated approach to model re-design for high throughput is key, with the limitations on throughput at each stage considered in order to develop a system which can deliver and analyse at high throughput rates at all stages of the process.