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1. On-chip Detection of Single Vesicle Release from Neuroblastoma Cells using Monolithic CMOS Bioelectronics

   https://doi.org/10.1109/EMBC.2018.8513219  

   White, Kevin A.; Mulberry, Geoffrey; Sugaya, Kiminobu; Kim, Brian N. (July 2018, 2018 40th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC))

   Neuroblastoma cells are often used as a cell model to study Parkinson's disease, which causes reduced dopamine release in substantia nigra, the midbrain that controls movements. In this paper, we developed a 1024-ch monolithic CMOS sensor array that has the spatiotemporal resolution as well as low-noise performance to monitor single vesicle release of dopamine from neuroblastoma cells. The CMOS device integrates 1024 on-chip electrodes with an individual size of 15 μm × 15 μm and 1024 transimpedance amplifiers for each electrode, which are each capable of measuring sub-pA current. Thus, this device can be used to study the detailed molecular dynamics of dopamine secretion at single vesicle resolution. 

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2. Rapid 1024-pixel Electrochemical Imaging at 10,000 Frames per Second using Monolithic CMOS Sensor and Multifunctional Data Acquisition System

   https://doi.org/10.1109/JSEN.2018.2835829  

   White, Kevin A.; Mulberry, Geoffrey; Kim, Brian N. (May 2018, IEEE Sensors Journal)

   Fast electrochemical imaging enables the dynamic study of electroactive molecule diffusion in neurotransmitter release from single cells and dopamine mapping in brain slices. In this paper, we discuss the design of an electrochemical imaging sensor using a monolithic CMOS sensor array and a multifunctional data acquisition system. Using post-CMOS fabrication, the CMOS sensor integrates 1024 on-chip electrodes on the surface and contains 1024 low-noise amplifiers to simultaneous process parallel electrochemical recordings. Each electrochemical electrode and amplifier are optimized to operate at 10.38 kHz sampling rate. To support the operation of the high-throughput CMOS device, a multifunctional data acquisition device is developed to provide the required speed and accuracy. The high analog data rate of 10.63 MHz from all 1024 amplifiers is redundantly sampled by the custom-designed data acquisition system which can process up to 73.6 MHz with up to ~400 Mbytes/s data rate to a computer using USB 3.0 interface. To contain the liquid above the electrochemical sensors and prevent electronic and wire damage, we packaged the monolithic sensor using a 3D-printed well. Using the presented device, 32 pixel × 32 pixel electrochemical imaging of dopamine diffusion is successfully demonstrated at over 10,000 frames per second, the fastest reported to date. 

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3. A 512-Ch Dual-Mode Microchip for Simultaneous Measurements of Electrophysiological and Neurochemical Activities

   https://doi.org/10.3390/bios13050502  

   Mulberry, Geoffrey; White, Kevin A.; Crocker, Matthew A.; Kim, Brian N. (May 2023, Biosensors)

   In the study of the brain, large and high-density microelectrode arrays have been widely used to study the behavior of neurotransmission. CMOS technology has facilitated these devices by enabling the integration of high-performance amplifiers directly on-chip. Usually, these large arrays measure only the voltage spikes resulting from action potentials traveling along firing neuronal cells. However, at synapses, communication between neurons occurs by the release of neurotransmitters, which cannot be measured on typical CMOS electrophysiology devices. Development of electrochemical amplifiers has resulted in the measurement of neurotransmitter exocytosis down to the level of a single vesicle. To effectively monitor the complete picture of neurotransmission, measurement of both action potentials and neurotransmitter activity is needed. Current efforts have not resulted in a device that is capable of the simultaneous measurement of action potential and neurotransmitter release at the same spatiotemporal resolution needed for a comprehensive study of neurotransmission. In this paper, we present a true dual-mode CMOS device that fully integrates 256-ch electrophysiology amplifiers and 256-ch electrochemical amplifiers, along with an on-chip 512 electrode microelectrode array capable of simultaneous measurement from all 512 channels. 

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4. Fully parallel 512-ch dual-mode electrophysiology and neurochemical amplifiers

   https://doi.org/10.1109/MWSCAS54063.2022.9859534  

   Mulberry, Geoffrey; White, Kevin A.; Kim, Brian N. (August 2022, Fully parallel 512-ch dual-mode electrophysiology and neurochemical amplifiers)

   The electrical potential recordings using a large microelectrode array from neuronal cultures has been widely used to monitor neural spike activities and cellular activities. However, this approach does not monitor neurochemical release, and therefore only contains indirect information regarding synaptic neurotransmission. At the synapses, these action potentials instigate the secretion of neurotransmitters. Neurochemical recordings, based on electrochemical methods, enable the direct monitoring of synaptic transmissions with single-vesicle resolution as well as the excellent temporal resolution in the microsecond scale. The neural spike activities and the neurotransmitter secretions are related; however, one cannot be used to predict the other because of the complex vesicle trafficking and exocytosis processes. Here, we present a dual-mode amplifier array which integrates 256-ch transconductance amplifiers and 256-ch transimpedance amplifiers. The dual-mode amplifier array enables the simultaneous recordings of electrophysiology and neurochemical activities. Capturing both neurochemical and neural spike (action potential and local field potential) activities would provide comprehensive spatiotemporal images of the brain activities. 

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5. Analysis of Discrete-Time Integrating Amplifiers as an Alternative to Continuous-Time Amplifiers in Broadband Receivers

   https://doi.org/10.1109/OJCAS.2023.3338210  

   Ray, Yudhajit; Sen, Shreyas (January 2023, IEEE Open Journal of Circuits and Systems)

   Recent advancements in low power and low noise front-end amplifiers have made it possible to support high-speed data transmission within the deep roll-off regions of conventional wireline channels. Despite being primarily limited by inter-symbol-interference (ISI), these legacy channels also require power-consuming front-end amplifiers due to increased insertion-loss at high frequencies. Wireline-like broadband channels, such as proximity communication and human-body-communication (HBC), as well as multi-lane, densely-packed channels, are further constrained by their high loss and unique channel responses which cause the received signal to be noise-limited. To address these challenges, this paper proposes the use of a discrete-time integrating amplifier as a low power <1 pJ/b using 65nm CMOS up to 5-6 Gb/s) alternative to traditional continuous-time front-end amplifiers. Integrating amplifiers also reduce the effects of noise due to its inherent current integrating process. The paper provides a detailed mathematical analysis of gain of two conventional and three novel and improved integrating amplifiers, accurate input referred noise estimations, signal-to-noise ratio, and a comparison of the integrating amplifier’s performance with that of a low-noise amplifier. The analysis identifies the most optimum integrator architecture and provides comparison with simulated results. This paper also develops theoretical expressions and provides in-depth understanding of input referred noise, while supporting them by simulations using 65nm CMOS technology node. Finally, a comparative analysis between low-noise amplifier and discrete-time integrating amplifier is presented to demonstrate power and noise benefits for both legacy and wireline-like channels, while providing an easier design space as integrator provides two-dimensional controllability for gain. 

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