Microfabricated Multimode Bio-interface with High Density Microelectrode Array and Photonic Detectors

Mohssen Moridi
EPFL, 2011
EPFL thesis

Abstract

Presently, the cells' electrical activity is measured either by extracellular microelectrode array (MEA) or by microscopic fluorescence imaging methods. The MEA is a non-invasive in vitro technique which allows long-term recording at multicellular level while fluorescence imaging technique enables to record the cells' action potential from subcellular to the organ level either in vivo or in vitro. These techniques have a number of limitations due to the fact that they require complex electro-optical recording equipment. As a matter of fact, because these systems are expensive, require skilled operators, suffer from problems of keeping the preparations under physiological conditions and permit to conduct only one experiment at a time, they are not suited for long-term and massively parallel measurements. In order to overcome these limitations, it would be highly desirable to obtain a hybrid sensor which combines simultaneous electrical and optical recording capabilities with sufficient spatiotemporal resolution to resolve distributed electrical activity and associated changes in intracellular ion concentrations, both at the single cell level and at the level of entire networks of excitable cells. The objective of this thesis is to design and to fabricate a novel type of hybrid sensor array which allows measuring simultaneously dynamic changes in the extracellular electrical potential and intracellular ion concentrations at a high spatiotemporal resolution. This is realised by a novel approach using a microfabricated glass interface, hereafter called bio-interface, between the electronic readout circuit and the cell network. This bio-interface features an array of 4096 implemented sensing elements, i.e., electrodes and photodiodes, on an area of 3.7 mm2. It is flip-chip bonded to an integrated circuit (IC) by means of high-density indium bumps forming a multi-mode sensor array (MMSA). The IC provides a selectable local amplification of the electrical signals sensed by the microelectrodes, photodetectors, and the processing capabilities to read out all pixels sequentially. The final goal of this work consists of the implementation of a fully operational and validated MMSA measurement platform, which can be used as core instrument for biological research projects. Since the fabricated MMSA essentially represents a microscope-less fluorescence imager with microscopic resolution and embedded electrical signal recording capabilities, it has the potential to turn into a new key measurement technique for both basic and applied biological research in fields as diverse as developmental biology, cardiac electrophysiology, neurophysiology, drug screening, and toxicological studies. This thesis demonstrates the design and fabrication process of the biointerface and the post-processing in connection with the IC and packaging issues. The bio-interface was successfully fabricated and flip-chip bonded to the readout electronics by means of high density indium bumps. These bumps feature a diameter of 15 µm at a 30 µm pitch. Tests show a bump yield of 100 %. The photodiode array was optically characterized and the device biocompatibility was validated by culturing a monolayer of cardiomyocytes on top of the bio-interface.

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Mohssen Moridi
EPFL, 2011
EPFL thesis

Abstract

Official source

https://infoscience.epfl.ch/record/166933?ln=en

About this result

Related concepts (23)

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Related publications

Low-Noise, High-Density Microelectronics for Multi-Mode Screening of Excitable Biological Cells

Urs Alexander Müller

In the past decades, two recording tools have established themselves as the working horses in the field of electrophysiological cell research: the microelectrode array (MEA) and the optical fluorescence imaging. The former is a grid of miniature electrodes allowing to monitor and stimulate cell networks; the latter uses voltage-sensitive dyes (VSDs) rendering the membrane potential visible. So far, researchers trying to combine these two measurement methods face complex electro-optical setups that suffer from the limitations of both techniques. On this ground, it is highly desirable to have a new tool at hand that (a) implements both measurement methods in a single device, (b) offers a high spatio-temporal resolution for both the electrical and the optical sensors, (c) is compact, (d) is easy to handle, and (e) allows long-term measurements. The project, this work is part of, aims to achieve these goals by means of a new concept: the multi-mode sensor array (MMSA). It consists of two parts: (1) a quartz-based microfabricated biointerface housing the sensing devices, i.e. platinum electrodes and amorphous silicon photodiodes; (2) an application specific integrated circuit (ASIC) for the amplification and the conditioning of the detected signals. The two devices are flip-chip bonded together by high-density indium bumps. The resulting measurement tool features a sensor array containing 1024 electrodes and 3072 photodiodes at a pitch of 60 μm and 30 μm, respectively. The main objective of this work is the development of said ASIC with the main task being the design of low-noise, high-density electronic circuits to read the signals detected by the biointerface electrodes and photodiodes. Secondary goals are the packaging of the system and the development of a data acquisition platform to visualise and analyse the measured values. In the course of this dissertation, two ASIC versions were designed: the MMSA I and MMSAII chips. With regard to the electrode low-noise amplifier (LNA), the two versions exhibit substantially different architectures. The MMSAI LNA features a fully-differential architecture, two amplification stages with selectable gain iii Abstract (60/50 dB) and a stable bandwidth of 10 kHz, and two integrated offset compensation techniques. While the measured gain and bandwidth are in good agreement with the simulations, the noise is substantially higher than anticipated since flicker noise was not taken into account in the circuit analysis. Based on the experiences from the MMSA I chip, the second ASIC was developed with a single-ended architecture with a folded-cascode amplifier at its core. It exhibits a gain of 52 dB, a bandwidth of 52 kHz, an average noise of 26 μVrms, and a power consumption of less than 85 μW. The offset compensation allows to deal with input-referred offset in a total range of 40 mV. Furthermore, each pixel was equipped with a sample & hold buffer and a programmable stimulation circuitry. The former stores the amplified signal locally thereby realising an electronic shutter for the electrode signals; the latter is centered around a SRAM (static random access memory) cell and permits the creation of complex stimulation patterns on the array. Comparing the design with literature reveals the competitiveness of the circuit in terms of noise efficiency factor versus area. For the treatment of the photodiode signals, the three-transistor active pixel sensor (APS) architecture is employed due to its simplicity and compactness. To maximise the sensitivity of the sensor, very small transistor dimensions were chosen, thereby minimising the capacitance. The measured responsivity ranges from 0.75 V/μWμs to 0.91 V/μWμs depending on the wavelenght of the incident light. The detectable amplitude can be adjusted by choosing an appropriate integration time. The developed package provides for the biocompatibility of the system, a stable casing, thermal dissipation, a container for the cell culture and nutrient solution, and modularity for easy exchange. The data acquisition platform transfers data at a rate of up to 35 MB/s to a computer via USB 2.0. Furthermore, it offers the creation of protocols to define the course of experiments including the choice of stimulation signal waveform, stimulation patterns, timing information, and recording options.

EPFL2012

In this thesis new imaging approaches for optical microscopy are proposed and studied. They are based on the use of dynamic structured illumination in combination with a demodulation detection concept employing CMOS image detectors. Two particular implementations are suggested: real-time optical sectioning microscopy and whole field quantitative polarization microscopy. Optical sectioning, i.e depth resolved imaging, allows observation of thin sections in volumetric samples. In its classical configuration the wide-field microscope does not allow optical sectioning of the investigated objects. In this thesis the optical sectioning in a wide-field microscope is achieved by illuminating the sample with a continuously moving single spatial frequency pattern, which temporarily modulates the signal obtained on the photodetector. Only the object parts that are in the focus have a good contrast and consequently generate stronger signal on the detector. The optically sectioned images are obtained employing a CMOS image detector, which demodulates the time-dependent component of the image. Two different systems for real-time acquisition of optically sectioned images are proposed. The first one is based on a specially designed smart-pixel-detector-array (SPDA), which allows performing the signal processing by an electronic circuit integrated to each pixel of the sensor. The second system utilizes a commercial CMOS image sensor. Here, the images are treated by a digital signal processor (DSP) integrated into the camera (iMVS-155). Both approaches provide real-time acquisition of optically sectioned images. The proof of principle for the new method is demonstrated by imaging artificial three-dimensional reflective samples. The optical sectioning imaging of biological samples in bright-field mode and in fluorescence mode is also demonstrated. The optical sectioning performances of the studied systems are similar to that of the confocal microscope. However the new method has some advantages over the classical confocal system: e.g. the difficulties with the alignment and the post-processing inherent to the confocal system are avoided. The theoretical framework presented in the thesis describes the image formation in structured illumination for both reflective and fluorescent samples. The influence of longitudinal chromatic aberration and spherical aberration caused by specimen induced index mismatch on depth discrimination property are studied. In extension to the work related to optically sectioned microscopy, the quantitative polarization microscopy imaging method is proposed as a new application for CMOS detectors. The polarization state of the illuminating light is dynamically changed and the demodulation detection approach is employed to extract the retardance and azimuth of the birefringent sample in real-time; for a whole field of view. Examples of polarization sensitive measurements for different samples are presented. The theoretical analysis is performed using the Jones formalism. Finally, the potentials and limitations of the CMOS detectors for applications in optical microscopy are discussed. Thanks to constant advancements in CMOS technology, the acquisition speed, resolution and sensitivity of new CMOS detectors generations have been improved. This will allow adapting the methods proposed in this thesis for investigations of fast dynamic process where high temporal and spatial resolution is required.

EPFL2004

Analysis and optimization of passive UHF RFID systems

Jari-Pascal Curty

Radio Frequency IDentification (RFID) is an automatic identification method, relying on storing and remotely retrieving data using devices called RFID tags or transponders. An RFID tag is a small object that can be attached to or incorporated into a product, animal or person. RFID tag contains antenna to enable it to receive and respond to Radio-Frequency (RF) queries from an RFID reader or interrogator. Passive tags require no internal power source, whereas active tags require a power source. As of today (2005), the ubiquitous computing and ambient intelligence ideas are making their way. In order for these to become a reality, a number of key technologies are required. Briefly, these technologies need to be sensitive, responsive, interconnected, contextualised, transparent and intelligent. RFID is such a technology and more particularly passive RFID tags. But, in order to deliver the necessary characteristics that could trigger ambient intelligence, there are some challenges that need to be addressed. Remote powering of the tags is probably the most important. Issues concerning the antenna-tag interface, as well as the rectifier design, that allows the RF signal to be converted to Direct Current (DC) are in pole position. Secondly, the communication link and the reader should be optimized. The RF signal that contains the tag data suffers from a power of four decay with the distance between tag and reader. As a result, both the reader sensitivity and the tag backscattered power efficiency have to be maximized. Long-range powering, as well as sufficient communication quality, are the guidelines of this work. This research project proposes a linear two-port model for an N-stage modified-Greinacher full wave rectifier. It predicts the overall conversion efficiency at low power levels where the diodes are operating near their threshold voltage. The output electrical behavior of the rectifier is calculated as a function of the received power and the antenna parameters. Moreover, the two-port parameters values are computed for particular input voltages and output currents for the complete N-stage rectifier circuit using only the measured I-V and C-V characteristics of a single diode. Also presented in this work is an experimental procedure to measure how the impedance modulation at the tag side affects the signal at the reader. The method allows the tag designer to efficiently predict the effect of modulator design at system level and gives an useful instrument to choose the most appropriate impedances. Finally, the design of a fully integrated remotely powered and addressable RFID tag working at 2.45 GHz is described. The achieved operating range at 4 W Effective Isotropically Radiated Power (EIRP) reader transmit power is 12 m. The Integrated Circuit (IC) is implemented in a 0.5 μm silicon-on-sapphire technology. A state of the art rectifier design achieving 37% of global efficiency is embedded to supply energy to the transponder. Inductive matching and a folded-dipole antenna are key elements to achieve these performances. The necessary input power to operate the transponder is about 2.7 μW.

EPFL2006