Electrical monitoring approaches in 3-dimensional cell culture systems: Toward label-free, high spatiotemporal resolution, and high-content data collection in vitro

3-dimensional (3D) cell cultures better mimic natural environment of cells than 2-dimensional (2D) cell cultures to obtain in vivo like inter and intracellular responses. However, third dimension brings complexity to cell culture. Therefore, high-resolution/high-content screening in 3D is one of the most important challenges with this type of cell cultures. Although optical monitoring techniques, well-established in 2D area, are enhanced to monitor 3D cell cultures, they are generally endpoint, static, time inefficient, and labor intensive. Alternatively, electrical sensing can become a solution to achieve dynamic, real-time, and label-free monitoring of cells in both 2D and 3D cell cultures. Developments in electrical monitoring of cell culture have led to novel approaches, proposed by adapting fundamentals of 2D electrical techniques to 3D to obtain high spatiotemporal systems. In this review, we classified these approaches into five main groups: (i) 3D impedance measurement approach (ii) electrical impedance tomography, (iii) 3D microelectrode array approach, (iv) 3D nanoelectronics scaffold approach, and (v) microphysiometry. We also defined the challenges in the adaptation of electrical monitoring techniques to 3D cultures and explained possible solutions in terms of specific applications and technical point of views, including methods particular to our group. In conclusion, 3D electrical monitoring in cell cultures is considerably challenging but highly accelerated recently by significant advances of microfabrication technology, bioengineering, and material science. Novel approaches reviewed here have a lot of potential and offer opportunities for further developments to find solutions, fit to serve the (bio)medical needs.