Design of custom CMOS amplifiers for nanoscale bio-interfaces

The miniaturization of electronics is a technique that holds a lot of potential in improving system performance in a variety of applications. The simultaneous miniaturization of sensors into the nano-scale has provided new ways to probe biological systems. Careful co-design of these electronics and sensors can unlock measurements and experiments that would otherwise be impossible to achieve. This thesis describes the design of two such instrumentation amplifiers and shows that significant gains in temporal resolution and noise performance are possible through careful optimization. A custom integrated amplifier is developed for improving the temporal resolution in nanopore recordings. The amplifier is designed in a commercial 0.18 μm complementary metal-oxide-semiconductor (CMOS) process. A platform is then built with the amplifier at its core that integrates glass-passivated solid-state nanopores to achieve measurement bandwidth over an order of magnitude greater than the state of the art. The use of wavelet transforms for denoising the data and further improving the signal-to-noise ratio (SNR) is then explored. A second amplifier is designed in a 0.18 μm CMOS process for intracellular recordings from neurons. The amplifier contains all the compensation circuitry required for canceling the effects of the electrode non-idealities. Compared to equivalent commercial systems and the state of the art, the amplifier performs comparably or better while consuming orders of magnitude lower power. These systems can inform the design of extremely miniaturized application-specific integrated amplifiers of the future

Micromachined three-dimensional electrode arrays for in-vitro and in-vivo electrogenic cellular networks

This dissertation presents an investigation of micromachined three-dimensional microelectrode arrays (3-D MEAs) targeted toward in-vitro and in-vivo biomedical applications. Current 3-D MEAs are predominantly silicon-based, fabricated in a planar fashion, and are assembled to achieve a true 3-D form: a technique that cannot be extended to micro-manufacturing. The integrated 3-D MEAs developed in this work are polymer-based and thus offer potential for large-scale, high volume manufacturing. Two different techniques are developed for microfabrication of these MEAs - laser micromachining of a conformally deposited polymer on a non-planar surface to create 3-D molds for metal electrodeposition; and metal transfer micromolding, where functional metal layers are transferred from one polymer to another during the process of micromolding thus eliminating the need for complex and non-repeatable 3-D lithography processes. In-vitro and in-vivo 3-D MEAs are microfabricated using these techniques and are packaged utilizing Printed Circuit Boards (PCB) or other low-cost manufacturing techniques. To demonstrate in-vitro applications, growth of 3-D co-cultures of neurons/astrocytes and tissue-slice electrophysiology with brain tissue of rat pups were implemented. To demonstrate in-vivo application, measurements of nerve conduction were implemented. Microelectrode impedance models, noise models and various process models were evaluated. The results confirmed biocompatibility of the polymers involved, acceptable impedance range and noise of the microelectrodes, and potential to improve upon an archaic clinical diagnostic application utilizing these 3-D MEAs.Ph.D.Committee Chair: Mark G. Allen; Committee Member: Elliot L. Chaikof; Committee Member: Ionnis (John) Papapolymerou; Committee Member: Maysam Ghovanloo; Committee Member: Oliver Bran

La nanoélectronique pour l'interfaçage neuronal : des nanofils de silicium à des dispositifs de carbone

In line with the technological progress of last decades a variety of adapted bioelectrical interfaces was developed to record electrical activity from the nervous system reaching from whole brain activity to single neuron signaling. Although neural interfaces have reached clinical utility and are commonly used in fundamental neuroscience, their performance is still limited. In this work we investigated alternative materials and techniques, which could improve the monitoring of neuronal activity of cultured networks, and the long-term performance of prospective neuroprosthetics. While silicon nanowire transistor arrays and diamond based microelectrodes are proposed for improving the spatial resolution and the electrode stability in biological environment respectively, the main focus of this thesis is set on the evaluation of graphene based field effect transistor arrays for bioelectronics. Due to its outstanding electrical, mechanical and chemical properties graphene appears as a promising candidate for the realization of chemically stable flexible electronics required for long-term neural interfacing. Here we demonstrate the outstanding neural affinity of pristine graphene and the realization of highly sensitive fast graphene transistors for neural interfaces.Dans la lignée des progrès technologiques récents en électronique, ces dernières décennies ont vu l’émergence d’une variété de systèmes permettant l’interface bioélectronique, allant de la mesure de l’activité électrique émise par l’ensemble du cerveau jusqu’à la mesure du signal émis par un neurone unique. Bien que des interfaces électroniques avec les neurones ont montré leur utilité pour des applications cliniques et sont communément utilisés par les neurosciences fondamentales, leurs performances sont encore très limitées, notamment en raison de l’incompatibilité relative entre les systèmes à l’état solide et le vivant. Dans ce travail de thèse, nous avons étudié des techniques et des matériaux nouveaux permettant une approche alternative et qui pourraient améliorer le suivi de l’activité de réseaux de neurones cultivés in situ et à terme la performance des neuroprothèses in vivo. Dans ce travail, des réseaux de nanofils de silicium et des microélectrodes en diamant sont élaborés pour respectivement améliorer la résolution spatiale et la stabilité des électrodes dans un environnement biologique. Un point important de cette thèse est également l’évaluation des performances de transistors à effet de champ en graphène pour la bio électronique. En raison des performances remarquables et combinées sur les aspects électrique, mécanique et chimique du graphène, ce matériau apparaît comme un candidat très prometteur pour la réalisation d’une électronique permettant une interface stable et sensible avec un réseau de neurones. Nous montrons dans ce travail l’affinité exceptionnelle des neurones avec une surface de graphène brut et la réalisation d’une électronique de détection rapide et sensible à base de transistor en graphène

Wireless Nano and Molecular Scale Neural Interfacing

Nanoscale circuits and sensors built from silicon nanowires, carbon nanotubes and other devices will require methods for unobtrusive interconnection with the macroscopic world to fully realise their potential; the size of conventional wires precludes their integration into dense, miniature systems. The same wiring problem presents an obstacle in our attempts to understand the brain by means of massively deployed nanodevices, for multiplexed recording and stimulation in vivo. We report on a nanoelectromechanical system that ameliorates wiring constraints, enabling highly integrated sensors to be read in parallel through a single output. Its basis is an effect in piezoelectric nanomechanical resonators that allows sensitive, linear and real-time transduction of electrical potentials. We interface multiple signals through a mechanical Fourier transform using tuneable resonators of different frequency and extract the signals from the system optically. With this method we demonstrate the direct transduction of neuronal action potentials from an extracellular microelectrode. We further extend this approach to incorporate nanophotonics for an all-optical system, coupled via a single optical fibre. Here, the mechanical resonators are both driven and probed optically, but modulated locally by the voltage sensors via the piezoelectric effect. Such piezophotonic nanoelectromechanical systems may be integrated with nanophotonic resonators, allowing concordant multiplexing in both the radiofrequency and optical bandwidths. In principle, this would allow billions of sensor channels to be multiplexed on an optical fibre. With view to eventually integrating such technology into a neural probe, we develop fabrication methods for crafting wired silicon neural probes via photolithography and electron beam lithography. Finally, to complement recording, we propose novel ideas for wireless, multiplexed neural stimulation through the use of radiofrequency-sensitive molecular scale resonators

Characterisation of CMOS APS Technologies for Space Applications

In recent years, the performance of scientific CMOS active pixel sensors has been improved to the point that it is now approaching that of the current silicon sensor of choice, CCDs. For some applications, CMOS APSs is believed to present significant advantages over CCDs, such as improved radiation hardness. In this work, the effect of radiation damage on a ‘baseline’ commercial APS, e2v technologies’ Jade APS, is characterised in response to gamma, proton and heavy ion irradiation. Specific performance problems encountered during this radiation characterisation, such as dark current non-uniformity under gamma irradiation, random telegraph signals under proton irradiation, and single event effects under heavy ion irradiation are described and analyzed. The X-ray spectroscopic imaging performance of the device is measured and compared to the Ocean Colour Imager APS test array showing progress towards a high frame rate spectroscopic X-ray imager for space science. The implications of these results for using similar devices in space applications are considered. Furthermore, possible novel techniques for measuring inter-pixel responsivity non-uniformity, heavy ion detection and spectroscopy, and measuring the dynamics of radiation-induced trap formation are discussed

Micro-optics for Opto-genetic Neuro-stimulation with Micro-LED Arrays

The breakthrough discovery of a nanoscale optically gated ion channel protein, Channelrhodopsin 2 (ChR2), in combination with a genetically expressed optically activated ion pump, Halorhodopsin, allowed the direct stimulation and inhibition of individual action potentials with light alone. This thesis describes the development of optics and micro-optics which when used with micro-led array sources, collects and projects light efficiently and uniformly onto such opto-genetically modified specimens. When used with enhanced light gated ion channels and pumps these systems allow us to further our understanding of both brain and visual systems. Micro-LED arrays permit spatio-temporal control of neuron stimulation on sub-millisecond timescales. However, micro-led arrays are disadvantaged by the broad-angular spread of their light emission and their low spatial fill factor. We present the design of macro and micro-optics systems for use with a micro-LED arrays consisting of a matrix of 25μm diameter micro-LEDs with 150 or 80μm centre-to-centre spacing. On one system, the micro-LED array is imaged onto off-the-shelf micro-optics using macro-optics and in the other system; micro-LED array and custom micro-optics are optimised and integrated together. The two systems are designed to improve the fill-factor from 2% to more than 78% by capturing a larger fraction of the LED emission and directing it correctly to the sample plane. This approach allows low fill factor arrays to be used effectively, which in turn has benefits in terms of thermal management and electrical drive from CMOS backplane electronics. These systems were implemented as an independent set that could be connected to a variety of different microscopes available for Patch-clamp and Multi-electrode measurements. As well, the feasibility of an eye prosthesis was tested using virtual reality optics and a fake eye to stimulate ganglion cells and by doing in-vivo stimulation of the genetically modified retina of a mouse.Open Acces

Microscopic imaging and photo-stimulation using micro-structured light emitting diodes

Imperial Users onl

A novel Three-Dimensional Micro-Electrode Array for in-vitro electrophysiological applications

Microelectrode arrays (MEAs) represent a powerful and popular tool to study in vitro neuronal networks and acute brain slices. The research standard for MEAs is planar or 2D-MEAs, which have been in existence for over 30 years and used for extracellular recording and stimulation from cultured neuronal cells and tissue slices. However, planar MEAs suffer from rapid data attenuation in the z-direction when stimulating/recording from 3D in-vitro neuronal cultures or brain slices. The existing proposed 3D in-vitro neuronal models allow to record the electrophysiological activity of the 3D network only from the bottom layer (i.e. the one directly coupled to the planar MEAs). Thus, to further develop and optimize such 3D neuronal network systems and to study and understand how the 3D neuronal network dynamics changes in different layers of the 3D structure, new three-dimensional microelectrodes arrays (3D-MEAs) are required. Early attempts in this field resulted in interesting integrated approaches toward protruding or spiked 3D-MEAs. Although these first prototypes could be successfully employed with brain slices, the limited heights of the electrodes (up to max 70 \u3bcm) and the peculiar shape of the recording areas made them not an ideal solution for 3D neuronal cultures. Moreover, a convenient and versatile method for the fabrication of multilevel 3D microelectrode arrays has yet to be obtained, due to the usually complicated and expensive designs and a lack of a full compatibility with standard MEAs both in terms of materials and recording area dimensions. To overcome the afore-mentioned challenges, in this work, I present the design, microfabrication, and characterization of a new 3D-MEA composed of pillar-shaped gold 3D structures with heights of more than 100 \u3bcm that can be used, in principle, on every kind of MEA, both custom-made and commercial. I successfully demonstrate the capability and ability of such 3D-MEA to record electrophysiological spontaneous activity from 3D engineered in-vitro neuronal networks and both 4-AP-induced epileptiform-like and electrically-evoked activity from mouse acute brain slices. I also demonstrate how the developed 3D-MEA allows better recording and stimulating conditions while interfacing with acute brain slices as compared to planar electrode arrays and previously reported 3D MEA technologies

Self-diagnosis implantable optrode for optogenetic stimulation

PhD ThesisAs a cell type-specific neuromodulation method, optogenetic technique holds remarkable potential for the realisation of advanced neuroprostheses. By genetically expressing light-sensitive proteins such as channelrhodopsin-2 (ChR2) in cell membranes, targeted neurons could be controlled by blue light. This new neuromodulation technique could then be applied into extensive brain networks and be utilised to provide effective therapies for neurological disorders. However, the development of novel optogenetic implants is still a key challenge in the field. The major requirements include small device dimensions, suitable spatial resolution, high safety, and strong controllability. In particular, appropriate implantable electronics are expected to be built into the device, accomplishing a new-generation intelligent optogenetic implant. To date, different microfabrication techniques, such as wave-guided laser/light-emitting diode (LED) structure and μLED-on-optrode structure, have been widely explored to create and miniaturise optogenetic implants. However, although these existing devices meet the requirements to some extent, there is still considerable room for improvement. In this thesis, a Complementary Metal-Oxide-Semiconductor (CMOS)-driven μLED approach is proposed to develop an advanced implantable optrode. This design is based on the μLED-on-optrode structure, where Gallium Nitride (GaN) μLEDs can be directly bonded to provide precise local light delivery and multi-layer stimulation. Moreover, an in-built diagnostic sensing circuitry is designed to monitor optrode integrity and degradation. This self-diagnosis function greatly improves system reliability and safety. Furthermore, in-situ temperature sensors are incorporated to monitor the local thermal effects of light emitters. This ensures both circuitry stability and tissue health. More importantly, external neural recording circuitry is integrated into the implant, which could observe local neural signals in the vicinity of the stimulation sites. Therefore, a CMOS-based multi-sensor optogenetic implant is achieved, and this closed-loop neural interface is capable of performing multichannel optical neural stimulation and electrical neural recording simultaneously. This optrode is expected to represent a promising neural interface for broad neuroprosthesis applications