Summary

OOAC devices are an emerging tool for testing novel and re-purposed drugs. Each chip contains hollow channels containing human cells and mechanical forces can be applied to mimic the physical micro-environment of living organs. All tissues in the body have an internal biological circadian ‘clock’ which co-ordinates cellular processes according to whether it is day or night, creating cycles of biological function every 24h. Circadian rhythms are not incorporated into current OOAC technology and there is no means of establishing the biological time of cells within these devices, limiting the therapeutic and commercial potential of the technology.

Drug efficacy and toxicity often varies according to the time of administration and ‘chronotherapeutics’ refers to optimising the timing of drug administration to maximise efficacy according to ‘biological time’. However, for the majority of treatments, the influence of biological time on therapeutic efficacy has not been studied or exploited.

Disruption of the circadian clock is a key risk factor for cardiovascular disease, a leading cause of death worldwide. Endothelial cells line the blood vessels and determine their health by controlling vascular permeability, blood pressure, clotting and inflammation. The timing of these functions is regulated by the circadian clock and medications targeting endothelial cell function must account for intrinsic cellular timing in order to fully interpret results of high-throughput screening platforms.

This study will enable the response of cells to the circadian clock to be measured allowing cellular circadian rhythms to be induced and monitored. This new biological tool will incorporate cellular time as a 4th dimension into OOAC devices.