An electrically-stimulate optically-record microsystem based on active CMOS multi-electrode array for dissociated cell cultures

Calcium fluorescence-based optical recording combined with patch-clamp stimulation has become the standard technique for analyzing neural network behavior. At best, stimulation is limited to only a few channels in this case. Passive multielectrode arrays for two-dimensional electrophysiology only offer electrode densities of 60 electrodes per mm². Here, we report an active multielectrode array, constructed with a standard complementary metal-oxide-semiconductor (CMOS) technology, to perform localized extracellular stimulation of dispersed cell cultures. A 256×256 array integrated with in-pixel stimulators on a 4-by-4 mm² CMOS chip noninvasively stimulate hippocampal cells cultured on chip at cellular resolution. Combined with calcium imaging using high-affinity indicators, we demonstrate the ability to observe spatiotemporal dynamics of neural activity.