Advancing Cell-Based Assays by Integration of Label-free Biosensors in Microfluidic Devices

Cell-based bioassays are a widely used research tool in biology and medicine to provide mechanistic insights into cellular functions. Although widely employed their technological advancement has stagnated over the last decade and most cell-based assays are still performed as end-point formats that makes monitoring of dynamic cell behavior cost and time intensive or even impossible. The recent trend towards more relevant cell-based assays has afforded new opportunities for label-free sensing methods. Label-free sensors are a promising tool to overcome existing limitation of end-point detection methods since they allow for continuous, non-invasive real-time monitoring of cell populations without the need for staining or other cell manipulation. We have recently integrated various label-free biosensors into microfluidic cell cultivation systems for whole cell monitoring. Non-invasive monitoring of cell cultures is accomplished by employing optical light scattering, bioluminescence and impedance spectroscopy to continuously detect cell numbers, cell-substrate interactions, cytotoxicity and metabolic activity as well as cell-cell interactions. Practical application of the developed microfluidic cell culture systems is demonstrated by monitoring oxygen consumption of cell monolayers and 3D cell aggregates as well as determining intracellular dynamics following exposure to inflammatory cytokines. Overall, the development, fabrication and characterization of optical and electrical label-free biosensors for cell population monitoring and their integration with microfluidic devices will be presented. Furthermore, the benefits of combining complementary label-free detections systems into a single device will be addressed to improve assay reproducibility, reliability and ability to clarify ambiguous assay results including toxicity tests and monitoring of co-culture interactions.