A CMOS-based Lab-on-Chip Array for the Combined Magnetic Stimulation and Opto-Chemical Sensing of Neural Tissue

This paper presents a novel CMOS-based lab-on-chip platform for non-contact magnetic stimulation and recording of neural tissue. The proposed system is the first of its kind to integrate magnetic-stimulation and opto-chemical sensing in a single pixel, tesselated to form an 8 à 8 array. Fabricated in a commercially-available 0.35 ¿m CMOS technology, the system can be intrinsically used for both optical imaging and pH sensing and includes mechanisms for calibrating out sensor variation and mismatch. In addition to sensory acquisition via an integrated 10-bit ADC, a 64-instruction spatiotemporal pattern generator has been embedded within the array for driving the microscale magnetic neural stimulation. In this application the ISFET-based sensors are used to capacitively-couple neuronal charge in close proximity to the floating gate. Optical imaging hardware has also been embedded to provide topographic detail of the neural tissue.Published versio

Fabricación y caracterización de electrodos nanoestructurados para interfaces neurales no invasivas de eficiencia mejorada

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Físicas, leída el 07-04-2022Neurological disorders produce serious cognitive and motor disabilities, and they account for 7% of total global disease burden, measured in disability‐adjusted life years. In addition, the life expectancy has been continuously growing during the last decades and, as a consequence, neurodegenerative disorders are becoming more prevalent representing a larger part of the healthcare efforts and expenses. Every year, treating brain conditions accounts for 35% of Europe’s disease burden with a yearly cost of €798.000 million. Despite the efforts performed in the medical and science fields, the cure for most of the neurological disorders is far from being achieved. One of the most efficient strategies to treat neurological disorders is the use of implanted electrodes to produce neural electrical stimulation. Furthermore, electrodes are one of the main neural interfaces used in diagnostics techniques, and for the study of the neural activity in basic investigation, in vitro and in vivo. Despite their enormous potential, these electrodes face nowadays limitations. Generally, they are too big, producing unspecific stimulation that can lead to secondary effects. Their size reduction is limited by the associated impedance increase, which restricts their charge‐injection to the tissue...Los trastornos neurológicos producen graves discapacidades cognitivas y motoras y suponen actualmente el 7% de la carga global de morbilidad, medida en años de vida ajustados por discapacidad. Además, el aumento progresivo en la esperanza de vida de las últimas décadas ha incrementado la prevalencia de las enfermedades neurodegenerativas, produciéndose una mayor demanda de recursos médicos y un incremento del coste económico asociado. Cada año, el tratamiento de enfermedades cerebrales supone el 35% del gasto total médico europeo, con un coste de 798.000millones de euros. A pesar de los esfuerzos realizados en medicina y otras ciencias, actualmente no existe una cura para la mayoría de las enfermedades neurológicas. Una de las terapias más utilizadas en clínica es la estimulación eléctrica neuronal con electrodos implantados. Los electrodos se usan extensamente en técnicas de diagnóstico y en el estudio de la actividad neuronal, in vitro e in vivo. Sin embargo, a pesar de su enorme potencial, su uso lleva asociadas algunas limitaciones. En general son grandes, por lo que la estimulación neuronal no es localizada, pudiendo producir efectos secundarios, y la reducción de su tamaño lleva asociada un incremento de su impedancia, reduciéndose su capacidad de inyección de carga...Fac. de Ciencias FísicasTRUEunpu

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

Chronic neural probe for simultaneous recording of single-unit, multi-unit, and local field potential activity from multiple brain sites

Drug resistant focal epilepsy can be treated by resecting the epileptic focus requiring a precise focus localization using stereoelectroencephalography (SEEG) probes. As commercial SEEG probes offer only a limited spatial resolution, probes of higher channel count and design freedom enabling the incorporation of macro and microelectrodes would help increasing spatial resolution and thus open new perspectives for investigating mechanisms underlying focal epilepsy and its treatment. This work describes a new fabrication process for SEEG probes with materials and dimensions similar to clinical probes enabling recording single neuron activity at high spatial resolution. Polyimide is used as a biocompatible flexible substrate into which platinum electrodes and leads are... The resulting probe features match those of clinically approved devices. Tests in saline solution confirmed the probe stability and functionality. Probes were implanted into the brain of one monkey (Macaca mulatta), trained to perform different motor tasks. Suitable configurations including up to 128 electrode sites allow the recording of task-related neuronal signals. Probes with 32 and 64 electrode sites were implanted in the posterior parietal cortex. Local field potentials and multi-unit activity were recorded as early as one hour after implantation. Stable single-unit activity was achieved for up to 26 days after implantation of a 64-channel probe. All recorded signals showed modulation during task execution. With the novel probes it is possible to record stable biologically relevant data over a time span exceeding the usual time needed for epileptic focus localization in human patients. This is the first time that single units are recorded along cylindrical polyimide probes chronically implanted 22 mm deep into the brain of a monkey, which suggests the potential usefulness of this probe for human applications

The rise of flexible electronics in neuroscience, from materials selection to in vitro and in vivo applications

Neuroscience deals with one of the most complicate system we can study: the brain. The huge amount of connections among the cells and the different phenomena occurring at different scale give rise to a continuous flow of data that have to be collected, analyzed and interpreted. Neuroscientists try to interrogate this complexity to find basic principles underlying brain electrochemical signalling and human/animal behaviour to disclose the mechanisms that trigger neurodegenerative diseases and to understand how restoring damaged brain circuits. The main tool to perform these tasks is a neural interface, a system able to interact with brain tissue at different levels to provide a uni/bidirectional communication path. Recently, breakthroughs coming from various disciplines have been combined to enforce features and potentialities of neural interfaces. Among the different findings, flexible electronics is playing a pivotal role in revolutionizing neural interfaces. In this work, we review the most recent advances in the fabrication of neural interfaces based on flexible electronics. We define challenges and issues to be solved for the application of such platforms and we discuss the different parts of the system regarding improvements in materials selection and breakthrough in applications both for in vitro and in vivo tests

Roadmap on semiconductor-cell biointerfaces.

This roadmap outlines the role semiconductor-based materials play in understanding the complex biophysical dynamics at multiple length scales, as well as the design and implementation of next-generation electronic, optoelectronic, and mechanical devices for biointerfaces. The roadmap emphasizes the advantages of semiconductor building blocks in interfacing, monitoring, and manipulating the activity of biological components, and discusses the possibility of using active semiconductor-cell interfaces for discovering new signaling processes in the biological world

Development of experimental setups for the characterization of the mechanoelectrical coupling of cells in vitro

The field of mechanobiology emerged from the many evidences that mechanical forces acting on cells have a central role in their development and physiology. Cells, in fact, convert such forces into biochemical activities and gene expression in a process referred as mechanotransduction. In vitro models that mimic cell environment also from the mechanical point of view represent therefore a key tool for modelling cell behaviour and would find many applications, e.g. in drug development and tissue engineering. In this work I introduce novel tools for the study of mechanotransduction. In particular, I present a system for the evaluation of the complex response of electrically active cells, such as neurons and cardiomyocytes. This system integrates atomic force microscopy, extracellular electrophysiological recording, and optical microscopy in order to investigate cell activity in response to mechanical stimuli. I also present cell scaffolds for the in vitro study of cancer. Obtained results, although preliminary, show the potential of the proposed systems and methods to develop accurate in vitro models for mechanobiology studies

Electrokinetic confinement of axonal growth for dynamically configurable neural networks

Axons in the developing nervous system are directed via guidance cues, whose expression varies both spatially and temporally, to create functional neural circuits. Existing methods to create patterns of neural connectivity in vitro use only static geometries, and are unable to dynamically alter the guidance cues imparted on the cells. We introduce the use of AC electrokinetics to dynamically control axonal growth in cultured rat hippocampal neurons. We find that the application of modest voltages at frequencies on the order of 10[superscript 5] Hz can cause developing axons to be stopped adjacent to the electrodes while axons away from the electric fields exhibit uninhibited growth. By switching electrodes on or off, we can reversibly inhibit or permit axon passage across the electrodes. Our models suggest that dielectrophoresis is the causative AC electrokinetic effect. We make use of our dynamic control over axon elongation to create an axon-diode via an axon-lock system that consists of a pair of electrode ‘gates’ that either permit or prevent axons from passing through. Finally, we developed a neural circuit consisting of three populations of neurons, separated by three axon-locks to demonstrate the assembly of a functional, engineered neural network. Action potential recordings demonstrate that the AC electrokinetic effect does not harm axons, and Ca[superscript 2+] imaging demonstrated the unidirectional nature of the synaptic connections. AC electrokinetic confinement of axonal growth has potential for creating configurable, directional neural networks.National Institutes of Health (U.S.) (R01 EUREKA Award R01-NS066352

Engineering Electromagnetic Systems for Next-Generation Brain-Machine Interface

MagnetoElectric Nanoparticles (MENPs) are known to be a powerful tool for a broad range of applications spanning from medicine to energy-efficient electronics. MENPs allow to couple intrinsic electric fields in the nervous system with externally controlled magnetic fields. This thesis exploited MENPs to achieve contactless brain-machine interface (BMIs). Special electromagnetic devices were engineered for controlling the MENPs’ magnetoelectric effect to enable stimulation and recording. The most important engineering breakthroughs of the study are summarized below. (I) Metastable Physics to Localize Nanoparticles: One of the main challenges is to localize the nanoparticles at any selected site(s) in the brain. The fundamental problem is due to the fact that according to the Maxwell’s equations, magnetic fields could not be used to localize ferromagnetic nanoparticles under stable equilibrium conditions. Metastable physics was used to overcome this challenge theoretically and preliminary results show the potential of single neuron localization in neural cell culture. 3D electromagnetic sources generated a time varying magnetic field pattern which effectively kept the nanoparticles in a metastable diamagnetic state. (II) Electromagnetic Systems to Locally Stimulate Neurons: Assuming a magnetoelectric coefficient of 1 V/cm/Oe, application of a 1000 Oe field can lead to a local electric field of 1000 V/cm, which can be sufficient to induce stimulation. Two approaches for achieving local stimulation relied on localization of nanoparticles and field profiles, respectively. The nanoparticles were localized via the aforementioned metastable physics. As for the field profiles, they were controlled by specially designed electromagnetic sources. Both approaches were used to achieve sub-mm firing in hippocampal cell cultures. This controllably induced neural firing was confirmed via standard calcium ion imaging and electroencephalography. (III) Engineering Electromagnetic Systems to Record Neural Activity with MENPs: A theoretical model was developed to use MENPs for contactless recording of local neural activity. With MENPs, neural firing from a 1 mm3 depth could generate a magnetic field of 100 pT a few millimeters above the skull. For comparison, this value is approximately 3 orders of magnitude higher than the field generated by the same brain volume without using MENPs, i.e., on the order of 100 fT. Such amplification of the magnetic field generated by MENPs has the potential to enable cost-effective magnetoencephalography (MEG) based brain imaging systems which could operate at room temperature in a shield-free environment