Development of a Dual-Mode CMOS Microelectrode Array for the Simultaneous Study of Electrochemical and Electrophysiological Activities of the Brain

Medical diagnostic devices are in high demand due to increasing cases of neurodegenerative diseases in the aging population and pandemic outbreaks in our increasingly connected global community. Devices capable of detecting the presence of a disease in its early stages can have dramatic impacts on how it can be treated or eliminated. High cost and limited accessibility to diagnostic tools are the main barriers preventing potential patients from receiving a timely disease diagnosis. This dissertation presents several devices that are aimed at providing higher quality medical diagnostics at a low cost. Brain function is commonly studied with systems detecting the action potentials that are formed when neurons fire. CMOS technology enables extremely high-density electrode arrays to be produced with integrated amplifiers for high-throughput action potential measurement systems while greatly reducing the cost per measurement compared to traditional tools. Recently, CMOS technology has also been used to develop high-throughput electrochemical measurement systems. While action potentials are important, communication between neurons occurs by the flow of neurotransmitters at the synapses, so measurement of action potentials alone is incapable of fully studying neurotransmission. In many neurodegenerative diseases the breakdown in neurotransmission begins well before the disease manifests itself. The development of a dual-mode CMOS device that is capable of simultaneous high-throughput measurement of both action potentials and neurotransmitter flow via an on-chip electrode array is presented in this dissertation. This dual-mode technology is useful to those studying the dynamic decay of the neurotransmission process seen in many neurodegenerative diseases using a low-cost CMOS chip. This dissertation also discusses the development of more traditional diagnostic devices relying on PCR, a method commonly used only in centralized laboratories and not readily available at the point-of-care. These technologies will enable faster, cheaper, more accurate, and more accessible diagnostics to be performed closer to the patient

Rapid 1024-Pixel Electrochemical Imaging At 10,000 Frames Per Second Using Monolithic Cmos Sensor And Multifunctional Data Acquisition System

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 complementary metal-oxide-semiconductor (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 is 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 universal serial bus 3.0 interface. To contain the liquid above the electrochemical sensors and prevent electronic and wire damage, we packaged the monolithic sensor using a 3-D 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

Rapid 1024-Pixel Electrochemical Imaging at 10,000 Frames Per Second Using Monolithic CMOS Sensor and Multifunctional Data Acquisition System

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 complementary metal-oxide-semiconductor (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 is 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 universal serial bus 3.0 interface. To contain the liquid above the electrochemical sensors and prevent electronic and wire damage, we packaged the monolithic sensor using a 3-D 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

A Half-Shared Transimpedance Amplifier Architecture For High-Throughput Cmos Bioelectronics

A common problem in single-cell measurement is the low-throughput nature of measurements. Monolithic CMOS microsystems have enabled many parallel measurements to take place simultaneously to increase throughput due to the integration of electrodes and amplifiers into a single chip. This paper explores a CMOS chip containing an array of 1024 parallel transimpedance amplifiers that takes advantage of a \u27half-shared\u27 operational amplifier architecture. This architecture splits a traditional 5-transistor operational amplifier into two, the inverting half and the non-inverting half. Splitting an amplifier into two allows for the non-inverting half to be \u27shared\u27 with several inverting halves, reducing the die area required for each individual amplifier. This allows for an increased number of amplifiers to be embedded into the same chip; in this case, 32 amplifiers are able to fit in the same space as 17 traditional 5-transistor operational amplifiers. The amplifiers exhibit low mismatch of 1.65 mV across the entire 1024 amplifier array, as well as high linearity in transimpedance gain. The technique will enable larger arrays to be created in future designs to allow electrophysiologists, among others, access to even higher-throughput measurement tools

On-Chip Detection Of Single Vesicle Release From Neuroblastoma Cells Using Monolithic Cmos Bioelectronics

Neuroblastoma cells are often used as a cell model to study Parkinson\u27s 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

Single-Cell Recording Of Vesicle Release From Human Neuroblastoma Cells Using 1024-Ch Monolithic Cmos Bioelectronics

Human neuroblastoma cells, SH-SY5Y, are often used as a neuronal model to study Parkinson\u27s disease and dopamine release in the substantia nigra, a midbrain region that plays an important role in motor control. Using amperometric single-cell recordings of single vesicle release events, we can study molecular manipulations of dopamine release and gain a better understanding of the mechanisms of neurological diseases. However, single-cell analysis of neurotransmitter release using traditional techniques yields results with very low throughput. In this paper, we will discuss a monolithically-integrated CMOS sensor array that has the low-noise performance, fine temporal resolution, and 1024 parallel channels to observe dopamine release from many single cells with single-vesicle resolution. The measured noise levels of our transimpedance amplifier are 415, 622, and 1083 fARMS, at sampling rates of 10, 20, and 30 kS/s, respectively, without additional filtering. Post-CMOS processing is used to monolithically integrate 1024 on-chip gold electrodes, with an individual electrode size of 15 μm × 15 μm, directly on 1024 transimpedance amplifiers in the CMOS device. SU-8 traps are fabricated on individual electrodes to allow single cells to be interrogated and to reject multicellular clumps. Dopamine secretions from 76 cells are simultaneously recorded by loading the CMOS device with SH-SY5Y cells. In the 42-s measurement, a total of 7147 single vesicle release events are monitored. The study shows the CMOS device\u27s capability of recording vesicle secretion at a single-cell level, with 1024 parallel channels, to provide detailed information on the dynamics of dopamine release at a single-vesicle resolution

Handheld Battery-Operated Sample Preparation Device For Qpcr Nucleic Acid Detections Using Simple Contactless Pouring

Sample preparation is an essential process that precedes nucleic acid detections which use quantitative polymerase chain reaction (qPCR). However, sample preparation is a labor-intensive process and requires skilled labor, thus limiting the public\u27s access in low-resource settings to many high-quality nucleic acid-based detection mechanisms. In this paper, we present a simple, handheld, battery-operated sample preparation device to minimize user\u27s involvement. The device uses a simple pouring method to process the DNA sample without pipetting or using disposable pipette tips. The developed device has a size of 12 × 8 × 8 cm3 and mass of only 364 g. The device is compared to gold standard methods, including magnetic bead-based and silica filter-based DNA extractions. For a short segment DNA target of 68 bp, the presented device captured 8.67× more DNA compared to that of the manual magnetic bead-based method. Because of automation, the measured capture efficiency is more consistent and has a smaller deviation between multiple repetitions than the manual method. To present a comprehensive, portable, battery-operated diagnostic system, the sample preparation device is tested in conjunction with a 3D-manufactured qPCR device. The test using three diluted target DNA samples, each spiked in whole blood (1×, 0.1×, and 0.01×), revealed a quantitative detection with ideal cycle threshold separations between the measurements. The combination of two devices will aid in resource-limited settings to promptly and accurately diagnose infections of patients

Monolithic Cmos-Based Neurotransmitter Detector For L024-Ch Simultaneous Recordings

Neuroblastoma cells are regularly used to study Parkinson\u27s disease, as they are suitable cell models. Specifically, the release of dopamine from neurssoblastoma cells is studied, as Parkinson\u27s disease lowers the amount of dopamine released within the sustantia nigra, a structure within the midbrain that is important for controlling movement. To further the ability to study dopamine release from neuroblastoma cells, we developed a monolithic CMOS sensor array containing 1024 on-chip electrodes. Each electrode is 15 μm × 15 μm and is paired with a dedicated transimpedance amplifier capable of measuring sub-pA current. The channels throughout the array have both low-noise performance and spatiotemporal resolution enabling the study of dopamine release from a single vesicle. The presented device is used to record dopamine release from the SH-SY5Y neuroblastoma cell line to demonstrate its efficacy. The device\u27s characteristics enable the study of the detailed molecular dynamics that occur during dopamine secretion