Development of real-time cellular impedance analysis system

The cell impedance analysis technique is a label-free, non-invasive method, which simplifies sample preparation and allows applications requiring unmodified cell retrieval. However, traditional impedance measurement methods suffer from various problems (speed, bandwidth, accuracy) for extracting the cellular impedance information. This thesis proposes an improved system for extracting precise cellular impedance in real-time, with a wide bandwidth and satisfactory accuracy. The system hardware consists of five main parts: a microelectrode array (MEA), a stimulation circuit, a sensing circuit, a multi-function card and a computer. The development of system hardware is explored. Accordingly, a novel bioimpedance measurement method coined digital auto balancing bridge method, which is improved from the traditional analogue auto balancing bridge circuitry, is realized for real-time cellular impedance measurement. Two different digital bridge balancing algorithms are proposed and realized, which are based on least mean squares (LMS) algorithm and fast block LMS (FBLMS) algorithm for single- and multi-frequency measurements respectively. Details on their implementation in FPGA are discussed. The test results prove that the LMS-based algorithm is suitable for accelerating the measurement speed in single-frequency situation, whilst the FBLMS-based algorithm has advantages in stable convergence in multi-frequency applications. A novel algorithm, called the All Phase Fast Fourier Transform (APFFT), is applied for post-processing of bioimpedance measurement results. Compared with the classical FFT algorithm, the APFFT significantly reduces spectral leakage caused by truncation error. Compared to the traditional FFT and Digital Quadrature Demodulation (DQD) methods, the APFFT shows excellent performance for extracting accurate phase and amplitude in the frequency spectrum. Additionally, testing and evaluation of the realized system has been performed. The results show that our system achieved a satisfactory accuracy within a wide bandwidth, a fast measurement speed and a good repeatability. Furthermore, our system is compared with a commercial impedance analyzer (Agilent 4294A) in biological experiments. The results reveal that our system achieved a comparable accuracy to the commercial instrument in the biological experiments. Finally, conclusions are given and the future work is proposed

Conditioning electrical impedance mammography system

A multi-frequency Electrical Impedance Mammography (EIM) system has been developed to evaluate the conductivity and permittivity spectrums of breast tissues, which aims to improve early detection of breast cancer as a non-invasive, relatively low cost and label-free screening (or pre-screening) method. Multi-frequency EIM systems typically employ current excitations and measure differential potentials from the subject under test. Both the output impedance and system performance (SNR and accuracy) depend on the total output resistance, stray and output capacitances, capacitance at the electrode level, crosstalk at the chip and PCB levels. This makes the system design highly complex due to the impact of the unwanted capacitive effects, which substantially reduce the output impedance of stable current sources and bandwidth of the data that can be acquired. To overcome these difficulties, we present new methods to design a high performance, wide bandwidth EIM system using novel second generation current conveyor operational amplifiers based on a gyrator (OCCII-GIC) combination with different current excitation systems to cancel unwanted capacitive effects from the whole system. We reconstructed tomography images using a planar E-phantom consisting of an RSC circuit model, which represents the resistance of extra-cellular (R), intra-cellular (S) and membrane capacitance (C) of the breast tissues to validate the performance of the system. The experimental results demonstrated that an EIM system with the new design achieved a high output impedance of 10MΩ at 1MHz to at least 3MΩ at 3MHz frequency, with an average SNR and modelling accuracy of over 80dB and 99%, respectively

Wideband Fully-Programmable Dual-Mode CMOS Analogue Front-End for Electrical Impedance Spectroscopy

This paper presents a multi-channel dual-mode CMOS analogue front-end (AFE) for electrochemical and bioimpedance analysis. Current-mode and voltage-mode readouts, integrated on the same chip, can provide an adaptable platform to correlate single-cell biosensor studies with large-scale tissue or organ analysis for real-time cancer detection, imaging and characterization. The chip, implemented in a 180-nm CMOS technology, combines two current-readout (CR) channels and four voltage-readout (VR) channels suitable for both bipolar and tetrapolar electrical impedance spectroscopy (EIS) analysis. Each VR channel occupies an area of 0.48 mm 2 , is capable of an operational bandwidth of 8 MHz and a linear gain in the range between -6 dB and 42 dB. The gain of the CR channel can be set to 10 kΩ, 50 kΩ or 100 kΩ and is capable of 80-dB dynamic range, with a very linear response for input currents between 10 nA and 100 μ A. Each CR channel occupies an area of 0.21 mm 2 . The chip consumes between 530 μ A and 690 μ A per channel and operates from a 1.8-V supply. The chip was used to measure the impedance of capacitive interdigitated electrodes in saline solution. Measurements show close matching with results obtained using a commercial impedance analyser. The chip will be part of a fully flexible and configurable fully-integrated dual-mode EIS system for impedance sensors and bioimpedance analysis

Electrical Impedance Tomography: From the Traditional Design to the Novel Frontier of Wearables

Electrical impedance tomography (EIT) is a medical imaging technique based on the injection of a current or voltage pattern through electrodes on the skin of the patient, and on the reconstruction of the internal conductivity distribution from the voltages collected by the electrodes. Compared to other imaging techniques, EIT shows significant advantages: it does not use ionizing radiation, is non-invasive and is characterized by high temporal resolution. Moreover, its low cost and high portability make it suitable for real-time, bedside monitoring. However, EIT is also characterized by some technical limitations that cause poor spatial resolution. The possibility to design wearable devices based on EIT has recently given a boost to this technology. In this paper we reviewed EIT physical principles, hardware design and major clinical applications, from the classical to a wearable setup. A wireless and wearable EIT system seems a promising frontier of this technology, as it can both facilitate making clinical measurements and open novel scenarios to EIT systems, such as home monitoring

Advances in Integrated Circuits and Systems for Wearable Biomedical Electrical Impedance Tomography

Electrical impedance tomography (EIT) is an impedance mapping technique that can be used to image the inner impedance distribution of the subject under test. It is non-invasive, inexpensive and radiation-free, while at the same time it can facilitate long-term and real-time dynamic monitoring. Thus, EIT lends itself particularly well to the development of a bio-signal monitoring/imaging system in the form of wearable technology. This work focuses on EIT system hardware advancement using complementary metal oxide semiconductor (CMOS) technology. It presents the design and testing of application specific integrated circuit (ASIC) and their successful use in two bio-medical applications, namely, neonatal lung function monitoring and human-machine interface (HMI) for prosthetic hand control. Each year fifteen million babies are born prematurely, and up to 30% suffer from lung disease. Although respiratory support, especially mechanical ventilation, can improve their survival, it also can cause injury to their vulnerable lungs resulting in severe and chronic pulmonary morbidity lasting into adulthood, thus an integrated wearable EIT system for neonatal lung function monitoring is urgently needed. In this work, two wearable belt systems are presented. The first belt features a miniaturized active electrode module built around an analog front-end ASIC which is fabricated with 0.35-µm high-voltage process technology with ±9 V power supplies and occupies a total die area of 3.9 mm². The ASIC offers a high power active current driver capable of up to 6 mAp-p output, and wideband active buffer for EIT recording as well as contact impedance monitoring. The belt has a bandwidth of 500 kHz, and an image frame rate of 107 frame/s. To further improve the system, the active electrode module is integrated into one ASIC. It contains a fully differential current driver, a current feedback instrumentation amplifier (IA), a digital controller and multiplexors with a total die area of 9.6 mm². Compared to the conventional active electrode architecture employed in the first EIT belt, the second belt features a new architecture. It allows programmable flexible electrode current drive and voltage sense patterns under simple digital control. It has intimate connections to the electrodes for the current drive and to the IA for direct differential voltage measurement providing superior common-mode rejection ratio (CMRR) up to 74 dB, and with active gain, the noise level can be reduced by a factor of √3 using the adjacent scan. The second belt has a wider operating bandwidth of 1 MHz and multi-frequency operation. The image frame rate is 122 frame/s, the fastest wearable EIT reported to date. It measures impedance with 98% accuracy and has less than 0.5 Ω and 1° variation across all channels. In addition the ASIC facilitates several other functionalities to provide supplementary clinical information at the bedside. With the advancement of technology and the ever-increasing fusion of computer and machine into daily life, a seamless HMI system that can recognize hand gestures and motions and allow the control of robotic machines or prostheses to perform dexterous tasks, is a target of research. Originally developed as an imaging technique, EIT can be used with a machine learning technique to track bones and muscles movement towards understanding the human user’s intentions and ultimately controlling prosthetic hand applications. For this application, an analog front-end ASIC is designed using 0.35-µm standard process technology with ±1.65 V power supplies. It comprises a current driver capable of differential drive and a low noise (9μVrms) IA with a CMRR of 80 dB. The function modules occupy an area of 0.07 mm². Using the ASIC, a complete HMI system based on the EIT principle for hand prosthesis control has been presented, and the user’s forearm inner bio-impedance redistribution is assessed. Using artificial neural networks, bio-impedance redistribution can be learned so as to recognise the user’s intention in real-time for prosthesis operation. In this work, eleven hand motions are designed for prosthesis operation. Experiments with five subjects show that the system can achieve an overall recognition accuracy of 95.8%

Design of ASIC Based Electrical Impedance Tomography Microendoscopic System for Prostate Cancer Surgical Marginal Assessment

Prostate cancer is the second most common cancer in the United States. It is typically treated by surgically excising the cancerous section of the prostate. Because there is not always a visible distinction between the healthy and cancerous sections, surgery often leaves some cancerous tissue behind. This is referred to as a positive surgical margin and it requires adjuvant treatment with adverse side effects. Electrical impedance tomography (EIT) is a low-cost low-form-factor method that can be used to assess surgical marginal intraoperatively to ensure that no cancerous tissue is left behind. EIT-based surgical margin assessment works on the principle that the electrical properties of cancerous tissue are different from those of healthy tissue. These differences are small at lower frequencies but become more pronounced at frequencies of 1 MHz and higher. Unfortunately, previous EIT solutions for surgical marginal assessment have been limited to operating frequencies of less than 1 MHz. This thesis presents a custom application-specific integrated circuit (ASIC) analog front end for performing EIT with a signal-to-noise ratio of 75 dB up to an operating frequency of 10 MHz. The custom ASIC was integrated into a 16-electrode EIT system for surgical marginal assessment. The entire system was tested on a saline phantom with a 2 mm bead that represented a cancerous lesion. The EIT system produced single-frequency and multi-frequency images showing the presence of the inclusion

The Investigation and Implementation of electrical Impedance Tomography Hardware System

Electrical impedance tomography (EIT) is a medical imaging technology that provides a tomographic representation of the distribution of electrical impedance within the body. As the electrical impedance varies for different body tissues, it is possible to characterize tissues from the images and to detect physiological events. EIT systems have been developed from applying a single signal frequency to a range of frequencies. Imaging at multiple frequencies significantly improves the ability to characterize and differentiate heterogeneity within the region of interest. Applications of EIT are limited by its poor resolution as a consequence of limited number of electrodes and lack of independently published measurements. In a practical EIT system design the parallel structure is normally adopted as it provides a real time monitoring structure. However, there is a difficulty in expanding to a 2-dimensitional or 3-dimensitional high resolution imaging system, as the number of electrodes increase. In this thesis, a serial structure spectrum EIT system has been investigated and developed. Modelling of the electrical circuit has shown that the system bandwidth is degraded primarily by the signal transmission in the coaxial cable and multiplexer. To remove the capacitive effect of these components, a distribute system concept has been developed. The concept uses active electrodes in which a current source and a front end amplifier are embedded in the electrode which makes direct contact with the tissue being measured. The active electrode is based on the Howland current source. The required high output impedance of Howland current source can be realised by matching the two resistor arms. However, from the electrical equivalent circuit analysis the actual output impedance of this circuit was found to be degraded by the op-amp' s limited open loop gain, especially at higher frequencies. To solve the problem, the author describes in detail a novel method of compensating for the above effects. Subsequent circuit tests showed significant improvement after the compensation. Further, to improve the small signal noise ratio a programmable gain amplifier to adapt the frame data measurement was developed. These developments have led to the feasibility of active electrodes. The thesis describes in detail the development, of the MK2 EIT system which is presented as the output of this research

MR-compatible Electrophysiology Recording System for Multimodal Imaging

Simultaneous acquisition of functional magnetic resonance imaging (fMRI) and electrophysiological recordings is an emerging multimodal neuroimaging strategy for studying brain functions. However, the strong magnetic field generated during fMRI greatly degrades the electrophysiological signal quality during simultaneous acquisition. Here, I developed a low powered, miniaturized, system – “ECHO” which delivers a hardware and software solution to overcome the challenges presented by multimodal imaging. The device monitors fluctuations in electromagnetic field during fMRI and synchronizes amplification and sampling of electrophysiological signals to minimize effects of gradient and RF artifacts (electromagnetic artifacts). Furthermore, I introduced a concept of wirelessly transmitting recorded data through the MRI receiver coil. ECHO transmits the data at a frequency visible to the MRI receiver coil, after which the transmitted data is readily separable from the MRI image in the frequency domain. The MR-compatibility of the recorder was evaluated through a series of experiments with a phantom to study its effects on the MRI image quality. To further evaluate the effectiveness of ECHO, I recorded electrocardiogram and local field potential (evoked potential) in live rats during concurrent fMRI acquisition. In summary, ECHO offers a ‘plug and play’ solution to capture artifact-free electrophysiological data without the need of expensive amplifiers or synchronization hardware which require physical connection to the MRI scanner. This device is expected to make multimodal imaging more accessible and be applied for a broad range of fMRI studies in both the research and clinical fields

CMOS Design of Reconfigurable SoC Systems for Impedance Sensor Devices

La rápida evolución en el campo de los sensores inteligentes, junto con los avances en las tecnologías de la computación y la comunicación, está revolucionando la forma en que recopilamos y analizamos datos del mundo físico para tomar decisiones, facilitando nuevas soluciones que desempeñan tareas que antes eran inconcebibles de lograr.La inclusión en un mismo dado de silicio de todos los elementos necesarios para un proceso de monitorización y actuación ha sido posible gracias a los avances en micro (y nano) electrónica. Al mismo tiempo, la evolución de las tecnologías de procesamiento y micromecanizado de superficies de silicio y otros materiales complementarios ha dado lugar al desarrollo de sensores integrados compatibles con CMOS, lo que permite la implementación de matrices de sensores de alta densidad. Así, la combinación de un sistema de adquisición basado en sensores on-Chip, junto con un microprocesador como núcleo digital donde se puede ejecutar la digitalización de señales, el procesamiento y la comunicación de datos proporciona características adicionales como reducción del coste, compacidad, portabilidad, alimentación por batería, facilidad de uso e intercambio inteligente de datos, aumentando su potencial número de aplicaciones.Esta tesis pretende profundizar en el diseño de un sistema portátil de medición de espectroscopía de impedancia de baja potencia operado por batería, basado en tecnologías microelectrónicas CMOS, que pueda integrarse con el sensor, proporcionando una implementación paralelizable sin incrementar significativamente el tamaño o el consumo, pero manteniendo las principales características de fiabilidad y sensibilidad de un instrumento de laboratorio. Esto requiere el diseño tanto de la etapa de gestión de la energía como de las diferentes celdas que conforman la interfaz, que habrán de satisfacer los requisitos de un alto rendimiento a la par que las exigentes restricciones de tamaño mínimo y bajo consumo requeridas en la monitorización portátil, características que son aún más críticas al considerar la tendencia actual hacia matrices de sensores.A nivel de celdas, se proponen diferentes circuitos en un proceso CMOS de 180 nm: un regulador de baja caída de voltaje como unidad de gestión de energía, que proporciona una alimentación de 1.8 V estable, de bajo ruido, precisa e independiente de la carga para todo el sistema; amplificadores de instrumentación con una aproximación completamente diferencial, que incluyen una etapa de entrada de voltaje/corriente configurable, ganancia programable y ancho de banda ajustable, tanto en la frecuencia de corte baja como alta; un multiplicador para conformar la demodulación dual, que está embebido en el amplificador para optimizar consumo y área; y filtros pasa baja totalmente integrados, que actúan como extractores de magnitud de DC, con frecuencias de corte ajustables desde sub-Hz hasta cientos de Hz.<br /

Electrical Impedance Tomography for Biomedical Applications: Circuits and Systems Review

There has been considerable interest in electrical impedance tomography (EIT) to provide low-cost, radiation-free, real-time and wearable means for physiological status monitoring. To be competitive with other well-established imaging modalities, it is important to understand the requirements of the specific application and determine a suitable system design. This paper presents an overview of EIT circuits and systems including architectures, current drivers, analog front-end and demodulation circuits, with emphasis on integrated circuit implementations. Commonly used circuit topologies are detailed, and tradeoffs are discussed to aid in choosing an appropriate design based on the application and system priorities. The paper also describes a number of integrated EIT systems for biomedical applications, as well as discussing current challenges and possible future directions