A 16×16 CMOS proton camera array for direct extracellular imaging of hydrogen-ion activity

Over the past twenty-five years, silicon CMOS technology has firmly established itself as the dominant platform in the microelectronics industry. This has resulted in many recent initiatives to fabricate CMOS-based microelectrodes for the stimulation and recording of electrical activity of neurons. CMOS technology offers the potential for monolithic integration of sensors and electronics and it serves as an appropriate platform to facilitate the integration of large arrays of sensors into a small geometry. The extracellular pH of a cell culture is a particularly important indicator of global cellular metabolism, but up until now, this property has typically been measured with invasive and expensive techniques such as miniaturized glass microelectrodes, fluorescent ratio imaging microscopy and magnetic resonance spectroscopy. CMOS provides a scalable, low cost, mass manufacturing platform, and offers the potential to develop sensor arrays that can perform non-invasive and long term imaging on cultured cells. In this paper, we present the first 16x16 proton camera array for direct imaging of the hydrogen-ion activity of cell cultures grown in vitro. The proton camera is based on a single-chip ion-sensitive field-effect transistor (ISFET) sensor array technology that can be implemented using a standard commercial CMOS process