1024-Ch Electrochemical Recordings of Single-cell Neurotransmitter Secretion from Human Neuroblastoma Cells Using Monolithic CMOS Bioelectronics

Through the study of neurotransmitter secretion at the single-vesicle resolution, we can advance the understanding of membrane fusion dynamics, the positive and negative side effects from drug treatments, and the mechanisms of neurological diseases on synaptic transmissions, such as Parkinson's disease. To monitor these rapid events from neurosecretory cells, on the scale of milliseconds or less, amperometry is widely used and has the fine temporal resolution necessary through oxidation of neurotransmitters at an electrode. However, traditional single-cell amperometry methods are low-throughput and time-consuming in order to gather a large set of data to develop statistically significant conclusions. In this work, a monolithic CMOS device is developed which integrates 1024 electrochemical detectors. The CMOS chip is designed with 1024 transimpedance amplifiers arranged in a 32 × 32 array and using post-CMOS fabrication, 1024 on-chip platinum microelectrodes are integrated onto the surface of the CMOS chip. The electrochemical detector array operates at a sampling rate of 10 kS/s (can operate as fast as 40 kS/s) and achieves a noise level of ∼450 fARMS when dry, and ∼ 2 pARMS when electrolytic solution is in contact. We successfully demonstrated massively parallelized neurotransmitter measurements from human neuroblastoma cells (SH-SY5Y), a cell model often used to study Parkinson's disease. A single set of measurements in less than a minute collected over 7000 secretion events at a single-vesicle resolution. The revealed characteristics of the SY5Y cells in our study show an average half-width of 1.63 ms, an average of 94 secretion events per cell, and an average of 1.86 attomoles of released neurotransmitter. We also demonstrated that this technology can be used to accelerate the studies of drug effects on exocytosis.