A Fully Differential CMOS Potentiostat

A CMOS potentiostat for chemical sensing in a noisy environment is presented. The potentiostat measures bidirectional electrochemical redox currents proportional to the concentration of a chemical down to pico-ampere range. The fully differential architecture with differential recording electrodes suppresses the common mode interference. A 200μm×200μm prototype was fabricated in a standard 0.35μm standard CMOS technology and yields a 70dB dynamic range. The in-channel analog-to-digital converter (ADC) performs 16-bit current-tofrequency quantization. The integrated potentiostat functionality is validated in electrical and electrochemical experiments

Recent Advances in Neural Recording Microsystems

The accelerating pace of research in neuroscience has created a considerable demand for neural interfacing microsystems capable of monitoring the activity of large groups of neurons. These emerging tools have revealed a tremendous potential for the advancement of knowledge in brain research and for the development of useful clinical applications. They can extract the relevant control signals directly from the brain enabling individuals with severe disabilities to communicate their intentions to other devices, like computers or various prostheses. Such microsystems are self-contained devices composed of a neural probe attached with an integrated circuit for extracting neural signals from multiple channels, and transferring the data outside the body. The greatest challenge facing development of such emerging devices into viable clinical systems involves addressing their small form factor and low-power consumption constraints, while providing superior resolution. In this paper, we survey the recent progress in the design and the implementation of multi-channel neural recording Microsystems, with particular emphasis on the design of recording and telemetry electronics. An overview of the numerous neural signal modalities is given and the existing microsystem topologies are covered. We present energy-efficient sensory circuits to retrieve weak signals from neural probes and we compare them. We cover data management and smart power scheduling approaches, and we review advances in low-power telemetry. Finally, we conclude by summarizing the remaining challenges and by highlighting the emerging trends in the field

Real-Time Telemetry System for Amperometric and Potentiometric Electrochemical Sensors

A real-time telemetry system, which consists of readout circuits, an analog-to-digital converter (ADC), a microcontroller unit (MCU), a graphical user interface (GUI), and a radio frequency (RF) transceiver, is proposed for amperometric and potentiometric electrochemical sensors. By integrating the proposed system with the electrochemical sensors, analyte detection can be conveniently performed. The data is displayed in real-time on a GUI and optionally uploaded to a database via the Internet, allowing it to be accessed remotely. An MCU was implemented using a field programmable gate array (FPGA) to filter noise, transmit data, and provide control over peripheral devices to reduce power consumption, which in sleep mode is 70 mW lower than in operating mode. The readout circuits, which were implemented in the TSMC 0.18-μm CMOS process, include a potentiostat and an instrumentation amplifier (IA). The measurement results show that the proposed potentiostat has a detectable current range of 1 nA to 100 μA, and linearity with an R2 value of 0.99998 in each measured current range. The proposed IA has a common-mode rejection ratio (CMRR) greater than 90 dB. The proposed system was integrated with a potentiometric pH sensor and an amperometric nitrite sensor for in vitro experiments. The proposed system has high linearity (an R2 value greater than 0.99 was obtained in each experiment), a small size of 5.6 cm × 8.7 cm, high portability, and high integration

Wide Dynamic Range CMOS Potentiostat for Amperometric Chemical Sensor

Presented is a single-ended potentiostat topology with a new interface connection between sensor electrodes and potentiostat circuit to avoid deviation of cell voltage and linearly convert the cell current into voltage signal. Additionally, due to the increased harmonic distortion quantity when detecting low-level sensor current, the performance of potentiostat linearity which causes the detectable current and dynamic range to be limited is relatively decreased. Thus, to alleviate these irregularities, a fully-differential potentiostat is designed with a wide output voltage swing compared to single-ended potentiostat. Two proposed potentiostats were implemented using TSMC 0.18-μm CMOS process for biomedical application. Measurement results show that the fully differential potentiostat performs relatively better in terms of linearity when measuring current from 500 pA to 10 uA. Besides, the dynamic range value can reach a value of 86 dB

Fully Integrated Biochip Platforms for Advanced Healthcare

Recent advances in microelectronics and biosensors are enabling developments of innovative biochips for advanced healthcare by providing fully integrated platforms for continuous monitoring of a large set of human disease biomarkers. Continuous monitoring of several human metabolites can be addressed by using fully integrated and minimally invasive devices located in the sub-cutis, typically in the peritoneal region. This extends the techniques of continuous monitoring of glucose currently being pursued with diabetic patients. However, several issues have to be considered in order to succeed in developing fully integrated and minimally invasive implantable devices. These innovative devices require a high-degree of integration, minimal invasive surgery, long-term biocompatibility, security and privacy in data transmission, high reliability, high reproducibility, high specificity, low detection limit and high sensitivity. Recent advances in the field have already proposed possible solutions for several of these issues. The aim of the present paper is to present a broad spectrum of recent results and to propose future directions of development in order to obtain fully implantable systems for the continuous monitoring of the human metabolism in advanced healthcare applications

Development of an On-Animal Separation Based Sensor using On-line Microdialysis Sampling Coupled to Microchip Electrophoresis with Electrochemical Detection

Microdialysis is a sampling technique that can be employed for the continuous monitoring of compounds both in vivo and in vitro. The online-coupling of microdialysis to microchip electrophoresis provides an attractive technology for near real time monitoring of drugs and neurotransmitters in pharmacokinetic and behavioral studies. These on-line systems for the analysis of microdialysis samples allow for the development of selective and sensitive separation based sensors with the capability of preserving high temporal resolution. Electrochemical detection is well suited for these separation-based sensors due to the possibility of integrating the working and reference electrodes directly into the chip as well as the availability of a miniaturized isolated potentiostat. This dissertation primarily focuses on the development of an on-animal separation-based sensor using microdialysis coupled to microchip electrophoresis with amperometric detection. The system consists of an on-line interface to couple the microdialysis to microchip electrophoresis, high voltage power supplies, and an electrically isolated potentiostat. Initial studies were focused on developing and fabricating an all glass microfluidic device. This system was evaluated in vitro for the continuous monitoring of the enzymatic production of hydrogen peroxide. The system was optimized for the in vivo analysis of nitrite on a freely roaming animal. The system incorporates telemetry for remote control, data acquisition, and has been optimized for the continuous on-line analysis of microdialysis samples obtained using a linear probe following nitroglycerin administration. The on-line microdialysis-microchip electrophoresis system was fabricated using an all glass substrate that includes an electrophoresis separation channel, integrated platinum working and reference electrodes, as well as an interface for direct coupling of the chip to the microdialysis probe. This dissertation describes the development of the integrated system including optimization of the electrophoresis conditions, injection of samples into the chip using the on-line microdialysis-microchip electrophoresis interface, and evaluation of the overall ruggedness of the system. The ultimate goal is to use the separation based sensor for on-animal in vivo analysis of drugs and neurotransmitters in order to correlate neurochemistry and/or metabolism with behavior in freely roaming animals

Development of a Microarray Biosensor for Real-Time and Continuous Measurement of Neurochemicals

Continuous simultaneous measurement of glutamate (GLU), an excitatory neurochemical, and γ-aminobutyric acid (GABA), an inhibitory neurochemical, constitutes one of the major challenges in neuroscientific research. Maintaining appropriate levels of GLU and GABA is important for normal brain functions. Abnormal levels of GLU and GABA are responsible for various brain dysfunctions, like epilepsy and traumatic brain injury. GLU and GABA being non-electroactive are challenging to detect in real-time. To date, GABA is detected mainly via microdialysis with a high performance liquid chromatography (HPLC) system that employs electrochemical (EC) and spectroscopic methodologies. However, these systems are bulky and unsuitable for real-time continuous monitoring. As opposed to microdialysis, biosensors are easy to miniaturize and are highly suitable for in-vivo studies. Unfortunately, this method requires a rather cumbersome process that relies on externally applied pre-reactors and reagents. Here, we report the design and implementation of a GABA microarray probe that operates on a newly conceived principle. It consists of two microbiosensors, one for GLU and one for GABA detection, modified with glutamate oxidase and GABASE enzymes, respectively. The detection of GABA by this probe is based upon the in-situ generation of α-ketoglutarate from the GLU oxidation that takes place at both microbiosensor sites. By simultaneously measuring and subtracting the H2O2 oxidation currents of GLU microbiosensor from GABA microbiosensor, GABA and GLU can be detected continuously in real-time in vitro and ex vivo. This mechanism happens without the addition of any externally applied reagents. We optimized our novel approach in commercially available ceramic-based probes. The GABA probe was successfully tested in an adult rat brain slice preparation. However, those electrodes are geometrically limited (we cannot have a sentinel site at the same spatial level as GLU and GABA sites). Keeping theseissues in mind, we have developed a microwire array sensor that is not only capable of simultaneous measurement of GLU and GABA, but is also able to track signal resulting from interferents (e.g. Ascorbic Acid, AA). The unique geometry enables these microwire probes to measure GLU, GABA and interferents in the same spatial level. A Simple fabrication procedure and easy integration with the existing amperometric systems allow us to use them in cell culture, brain tissue, and in vivo recordings as an inexpensive alternative to our planar electrodes. We demonstrated the effectiveness of the probes in rat brain tissue. We were able to get. Additionally, we determined the excitation/inhibition (E/I) ratios for different stimulations which have clinical relevance. Our results about this E/I balance can help refine electrical stimulation parameter for different clinical purposes (e.g. deep brain stimulation). Finally, we successfully tested our probe in awake-free behaving rats. In summary, our results suggest that microwire probes have the potential to become a powerful tool for measuring GLU and GABA in various ex-vivo and in-vivo disease models, such as epilepsy

Neural Biosensor Probes for Simultaneous Electrophysiological Recordings, Neurochemical Measurements, and Drug Delivery with High Spatial and Temporal Resolution.

The aim of this work is to develop and validate novel neural biosensor probes for simultaneous electrophysiological and neurochemical measurements with precise, localized drug delivery. This technology has been developed to interface with the complex environment of the brain for more advanced experimental investigations at the intersections of neurophysiology, neuropathology, and neuropharmacology. The validation experiments have been conducted using relevant in vivo testbeds as a foundation for future work to more fully understand and treat neurological disorders. Chapter II presents a multimodal probe that enables concurrent detection of choline, recording of electrophysiology, and localized drug delivery. Central to this work is the development of selective electrodeposition methods for enzyme immobilization and polymerization on individual microelectrode sites that more closely approach the scale of neurons than currently reported neural biosensors. Multiple neurotransmitter systems are implicated in the pathophysiology of schizophrenia, Alzheimer’s disease, Parkinson’s disease, and other neurological disorders, yet the direct relationships remain unclear. The ability to simultaneously monitor multiple chemical signals concurrently with electrophysiology and integrated pharmacological manipulation can serve as a useful tool to further these investigations. Chapter III further extends the probe capabilities to include glutamate sensing concurrent with choline sensing, electrophysiology recordings, and drug delivery. Electrochemical biosensors are commonly used to record neurotransmitter dynamics, yet there remains no standard calibration media or procedure. Differences in calibration procedures can impact reported performance making the interpretation of in vivo difficult. Chapter IV aims to improve our ability to interpret in vivo neurochemical recordings by investigating the influence of calibration media on performance characteristics of amperometric biosensors. Bridging the electrophysiological and neurochemical domains with sufficient fidelity, resolution, sensitivity, and selectivity can provide novel insights into neurophysiology that lead to improved therapeutic approaches for treating neurologicalvdisorders.Ph.D.Biomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/89722/1/mattgib_1.pd

Microelectronics-Based Biosensors Dedicated to the Detection of Neurotransmitters: A Review

Dysregulation of neurotransmitters (NTs) in the human body are related to diseases such as Parkinson's and Alzheimer's. The mechanisms of several neurological disorders, such as epilepsy, have been linked to NTs. Because the number of diagnosed cases is increasing, the diagnosis and treatment of such diseases are important. To detect biomolecules including NTs, microtechnology, micro and nanoelectronics have become popular in the form of the miniaturization of medical and clinical devices. They offer high-performance features in terms of sensitivity, as well as low-background noise. In this paper, we review various devices and circuit techniques used for monitoring NTs in vitro and in vivo and compare various methods described in recent publications