Cellular sensing platform with enhanced sensitivity based on optogenetic modulation of cell homeostasis

We demonstrate a new biosensing concept with impact on the development of rapid, point of need cell based sensing with boosted sensitivity and wide relevance for bioanalysis. It involves optogenetic stimulation of cells stably transfected to express light sensitive protein channels for optical control of membrane potential and of ion homeostasis. Time-lapse impedance measurements are used to reveal cell dynamics changes encompassing cellular responses to bioactive stimuli and optically induced homeostasis disturbances. We prove that light driven perturbations of cell membrane potential induce homeostatic reactions and modulate transduction mechanisms that amplify cellular response to bioactive compounds. This allows cell based biosensors to respond more rapidly and sensitively to low concentrations of bioactive/toxic analytes: statistically relevant impedance changes are recorded in less than 30 min, in comparison with >8 h in the best alternative reported tests for the same low concentration (e.g. a concentration of 25 μM CdCl2, lower than the threshold concentration in classical cellular sensors). Comparative analysis of model bioactive/toxic compounds (ouabain and CdCl2) demonstrates that cellular reactivity can be boosted by light driven perturbations of cellular homeostasis and that this biosensing concept is able to discriminate analytes with different modes of action (i.e. CdCl2 toxicity versus ion pump inhibition by ouabain), a significant advance against state of the art cell based sensors. •A sensitive cellular platform with light-modulated cell homeostasis is achieved.•Characteristic cell responses are induced by light actuation per se and when accompanying the exposure to model analytes. ● Time lapse electrical impedance assays are used to quantitatively assess the dynamics of cellular effects in 1 h protocols.•Light induced cell perturbation increases the sensitivity to bioactive compounds.•A new live cell assay with inner referencing for fast, sensitive bioanalysis (low concentration, short exposure) is validated.