Modulating and Monitoring Autonomic Nerves for Glycemic Control

Diabetic patients suffer from a long-term condition that results in high blood glucose levels (hyperglycemia). Many medications for diabetes lose their glycemic control effectiveness over time and patient compliance to these medications is a major challenge. Glycemic control is a vital continuous process and is innately regulated by the endocrine and autonomic nervous systems. There is an opportunity for developing an implantable and automated treatment for diabetic patients by accurately detecting and altering neural activity in autonomic nerves. Renal nerves provide neural control for glucose reabsorption in the kidneys, and the vagus nerve conveys important glucose regulation signals to and from the liver and pancreas. This dissertation investigated stimulation of renal nerves for glycemic control, assembled an implantation procedure for neural interface arrays designed for autonomic nerves, and recorded physiological action potential signals in the vagus nerve. In a first study, stimulation of renal nerves in anesthetized, normal rats at kilohertz frequency (33 kHz) showed a notable average increase in urine glucose excretion (+24.5%). In contrast, low frequency (5 Hz) stimulation of renal nerves showed a substantial decrease in urine glucose excretion (−40.4%). However, these responses may be associated with urine flow rate. In a second study, kilohertz frequency stimulation (50 kHz) of renal nerves in anesthetized, diabetic rats showed a significant average decrease (-168.4%) in blood glucose concentration rate, and an increase (+18.9%) in the overall average area under the curve for urine glucose concentration, with respect to values before stimulation. In a third study, an innovative procedure was assembled for the chronic implantation of novel intraneural MIcroneedle Nerve Arrays (MINAs) in rat vagus nerves. Two array attachment approaches (fibrin sealant and rose-bengal bonding) were investigated to secure non-wired MINAs in nerves. The fibrin sealant approach was unsuccessful in securing the MINA-nerve interface for 4- and 8-week implant durations. The rose-bengal coated MINAs were in close proximity to axons (≤ 50 μm) in 75% of 1-week and 14% of 6-week implants with no significant harm to the implanted nerves or the overall health of the rats. In a fourth study, physiological neural activity in the vagus nerve of anesthetized rats was recorded using Carbon Fiber Microelectrode Arrays (CFMAs). Neural activity was observed on 51% of inserted functional carbon fibers, and 1-2 neural clusters were sorted on each carbon fiber with activity. The mean peak-to-peak amplitudes of the sorted clusters were 15.1-91.7 µV with SNR of 2.0-7.0. Conducting signals were detected in the afferent direction (0.7-1.0 m/sec conduction velocities) and efferent direction (0.7-8.8 m/sec). These conduction velocities are within the conduction velocity range of unmyelinated and myelinated vagus fibers. Furthermore, changes in vagal nerve activity were monitored in breathing and blood glucose modulated conditions. This dissertation, to our knowledge, was the first to demonstrate glucose regulation benefits by stimulation of renal nerves, chronically implant intraneural arrays in rat vagus nerves, and record physiological action potential in vagus nerves using multi-channel intraneural electrodes. Future work is needed to evaluate the long-term glucose regulation benefits of stimulation of renal nerves, and assess the tissue reactivity and recording integrity of implanted intraneural electrodes in autonomic nerves. This work supports the potential development of an alternative implantable treatment modality for diabetic patients by modulating and monitoring neural activity in autonomic nerves.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/155245/1/ajiman_1.pd

Designing A Platform to Detect Peripheral Neuropathy with Microneedle Electrodes and Neurophysiology

The growing obesity pandemic has caused diabetes to become one of the world’s leading health concerns. Diabetic individuals often suffer from peripheral neuropathy, which is nerve death that typically starts at the extremities and moves from the skin inward to deeper tissues. This nerve death causes painful symptoms including tingling, stinging, numbness, and others. Current methods to diagnose peripheral neuropathy by measuring nerve function are invasive and painful since they target large axons of the legs; however, by the time the neuropathy reaches the diagnosable axons, it is often too late for intervention. Although no cures for neuropathy are established, aside from analgesics for pain, there are options for mitigating worsening of the disease if diagnosed early enough (for example, glucose control for diabetic neuropathy). There is a critical need for early detection and diagnosis of peripheral neuropathy as obesity and diabetes continue to plague the world. Microneedle fabrication is a growing research area, especially in transdermal drug delivery due to their minimal invasive, pain-free application. The objective of this project is to design a platform using electrically conductive microneedles for early detection of peripheral neuropathy. Using these needles, neurophysiology can be employed to record electrical signal just below the skin to determine the integrity of the nerves to track neuropathy progression. Thus far, prototypes of the device have been tested on mice to establish protocols and understand the hardware and software, with the goal of eventually developing a usable prototype for a longitudinal study of diseased mice and human clinical studies

FLEXIBLE NEURAL INTERFACES FOR RECORDING AND STIMULATION OF PERIPHERAL AND VISCERAL NERVES

Ph.DDOCTOR OF PHILOSOPH

Low-dimensional representations of neural time-series data with applications to peripheral nerve decoding

Bioelectronic medicines, implanted devices that influence physiological states by peripheral neuromodulation, have promise as a new way of treating diverse conditions from rheumatism to diabetes. We here explore ways of creating nerve-based feedback for the implanted systems to act in a dynamically adapting closed loop. In a first empirical component, we carried out decoding studies on in vivo recordings of cat and rat bladder afferents. In a low-resolution data-set, we selected informative frequency bands of the neural activity using information theory to then relate to bladder pressure. In a second high-resolution dataset, we analysed the population code for bladder pressure, again using information theory, and proposed an informed decoding approach that promises enhanced robustness and automatic re-calibration by creating a low-dimensional population vector. Coming from a different direction of more general time-series analysis, we embedded a set of peripheral nerve recordings in a space of main firing characteristics by dimensionality reduction in a high-dimensional feature-space and automatically proposed single efficiently implementable estimators for each identified characteristic. For bioelectronic medicines, this feature-based pre-processing method enables an online signal characterisation of low-resolution data where spike sorting is impossible but simple power-measures discard informative structure. Analyses were based on surrogate data from a self-developed and flexibly adaptable computer model that we made publicly available. The wider utility of two feature-based analysis methods developed in this work was demonstrated on a variety of datasets from across science and industry. (1) Our feature-based generation of interpretable low-dimensional embeddings for unknown time-series datasets answers a need for simplifying and harvesting the growing body of sequential data that characterises modern science. (2) We propose an additional, supervised pipeline to tailor feature subsets to collections of classification problems. On a literature standard library of time-series classification tasks, we distilled 22 generically useful estimators and made them easily accessible.Open Acces

Carbon Fiber Electrode Arrays for Cortical and Peripheral Neural Interfaces

Neural interfaces create a connection between neural structures in the body and external electronic devices. Brain-machine interfaces and bioelectric medicine therapies rely on the seamless integration of neural interfaces with the brain, nerves, or spinal cord. However, conventional neural interfaces cannot meet the demands of high channel count, signal fidelity, and signal longevity that these applications require. I investigated the damage resulting from conventional Utah arrays after multiple years of implantation in the cortex of a non-human primate as a possible explanation for these limitations. The neuron density around the electrode shanks was compared to the neuron density of nearby healthy tissue, finding a 73% loss in density around the electrodes. The explanted arrays were imaged and characterized for degradation. Coating cracks, tip breakage, and parylene cracks were the most common degradation type. A significantly higher number of tip breakage and coating crack occurrences were found on the edges of the arrays as compared to the middle. In this work, I made clear the need for a minimally damaging alternative to the Utah electrode array. Neural interfaces composed of carbon fiber electrodes, with a diameter of 6.8 microns, could enable a seamless integration with the body. Previous work resulted in an array of individuated carbon fiber electrodes that reliably recorded high signal-to-noise ratio neural signals from the brain for months. However, the carbon fiber arrays were limited by only 30% of the electrodes recording neural signals, despite inducing minimal inflammation. Additionally, it was relatively unknown if carbon fibers would make suitable long-term peripheral neural interfaces. Here, I illustrate the potential of carbon fiber electrodes to meet the needs of a variety of neural applications. First, I optimized state-of-the-art carbon fiber electrodes to reliably record single unit electrophysiology from the brain. By analyzing the previous manufacturing process, the cause of the low recording yield of the carbon fiber arrays was identified as the consistency of the electrode tip. A novel laser cutting technique was developed to produce a consistent carbon fiber tip geometry, resulting in a near tripling of recording yield of high amplitude chronic neural signals. The longevity of the carbon fiber arrays was also addressed. The conventional polymer coating was compared against platinum iridium coating and an oxygen plasma treatment, both of which outperformed the polymer coating. In this work, I customized carbon fiber electrodes for reliable, long-term neural recording. Secondly, I translated the carbon fiber technology from the brain to the periphery in an architecture appropriate for chronic implantation. The insertion of carbon fibers into the stiffer structures in the periphery is enabled by sharpening the carbon fibers. The sharpening process combines a butane flame to sharpen the fibers with a water bath to protect the base of the array. Sharpened carbon fiber arrays recorded electrophysiology from the rat vagus nerve and feline dorsal root ganglia, both structures being important targets for bioelectric medicine therapies. The durability of carbon fibers was also displayed when partially embedded carbon fibers in medical-grade silicone withstood thousands of repeated bends without fracture. This work showed that carbon fibers have the electrical and structural properties necessary for chronic application. Overall, this work highlights the vast potential of carbon fiber electrodes. Through this thesis, future brain-machine interfaces and bioelectric medicine therapies may utilize arrays of sub-cellular electrodes such as carbon fibers in medical applications.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/169982/1/elissajw_1.pd

Doctor of Philosophy

dissertationOptical methods are well-established in the fields of neuroscience, medical imaging, and diagnostics, etc. Optogenetics, for example, enables molecular specificity in optical neural stimulation and recording and has been named the "Method of the Year 2010" by Nature Methods. A novel microdevice was designed, fabricated, developed, and tested to facilitate three-dimensional (3D) deep-tissue light penetration with the capacity to accommodate spatiotemporal modulation of one or more wavelengths to advance a broad range of applications for optical neural interfaces. A 3D optrode array consisting of optically transparent "needles" can penetrate >1 mm directly into tissue, thereby creating multiple independent paths for light propagation that avoid attenuation due to tissue absorption and scattering, providing a high level of selectivity and comprehensive access to tissue not available in current interfaces. Arrays were developed based upon silicon and glass. The silicon optrode array is based upon the well-established Utah electrode array architectures and is suitable for near-infrared (NIR) applications; glass optrodes are appropriate waveguides for both visible and NIR wavelengths. Arrays were bulk-micromachined with high-aspect ratio, a process that has not been reported to be applied to glass previously. In addition to device fabrication, extensive laboratory testing was performed with various optical sources to determine loss mechanisms and emitted beam profiles in tissue across the relevant wavelength ranges, with particular focus on performance metrics for optogenetic and infrared neural stimulation applications. Optrode arrays were determined to be amenable to integration with typical neural stimulation and imaging light delivery mechanisms such as optical fibers and microscopes. Glass optrodes were able to transmit light at ~90% efficiency through depths many times greater than the tissue attenuation length, with negligible light in-coupling loss. Si optrodes were determined to be only ~40% efficient with losses mostly from high index contrast, tip backreflection, and taper radiation. The in-coupling technique and optrode geometry may be modified to produce illumination volumes appropriate for various experimental paradigms. While the focus of this work is on optical neural stimulation, optrode array devices have application in basic neuroscience research, highly selective photodynamic therapy, and deep tissue imaging for diagnostics and therapy

Conformable transistors for bioelectronics

The diversity of network disruptions that occur in patients with neuropsychiatric disorders creates a strong demand for personalized medicine. Such approaches often take the form of implantable bioelectronic devices that are capable of monitoring pathophysiological activity for identifying biomarkers to allow for local and responsive delivery of intervention. They are also required to transmit this data outside of the body for evaluation of the treatment’s efficacy. However, the ability to perform these demanding electronic functions in the complex physiological environment with minimum disruption to the biological tissue remains a big challenge. An optimal fully implantable bioelectronic device would require each component from the front-end to the data transmission to be conformable and biocompatible. For this reason, organic material-based conformable electronics are ideal candidates for components of bioelectronic circuits due to their inherent flexibility, and soft nature. In this work, first an organic mixed-conducting particulate composite material (MCP) able to form functional electronic components and non-invasively acquire high–spatiotemporal resolution electrophysiological signals by directly interfacing human skin is presented. Secondly, we introduce organic electrochemical internal ion-gated transistors (IGTs) as a high-density, high-amplification sensing component as well as a low leakage, high-speed processing unit. Finally, a novel wireless, battery-free strategy for electrophysiological signal acquisition, processing, and transmission that employs IGTs and an ionic communication circuit (IC) is introduced. We show that the wirelessly-powered IGTs are able to acquire and modulate neurophysiological data in-vivo and transmit them transdermally, eliminating the need for any hard Si-based electronics in the implant

Implantable microelectrodes on soft substrate with nanostructured active surface for stimulation and recording of brain activities

Les prothèses neuronales implantables offrent de nos jours une réelle opportunité pour restaurer des fonctions perdues par des patients atteints de lésions cérébrales ou de la moelle épinière, en associant un canal non-musculaire au cerveau ce qui permet la connexion de machines au système nerveux. La fiabilité sur le long terme de ces dispositifs, se présentant sous la forme d'électrodes implantables, est un facteur crucial pour envisager des applications dans le domaine des interfaces cerveau-machine. Cependant, les électrodes actuelles pour l'enregistrement et la stimulation se détériorent en quelques mois voire quelques semaines. Ce défaut de fiabilité sur le long terme, principalement lié à une réaction chronique contre un corps étranger, est induit au départ par le traumatisme consécutif à l'insertion du dispositif et s'aggrave ensuite, durant les mouvements du cerveau, à cause des propriétés mécaniques inadaptées de l'électrode par rapport à celles du tissu. Au cours du temps, l'ensemble de ces facteurs inflammatoires conduit à l'encapsulation de l'électrode par une couche isolante de cellules réactives détériorant ainsi la qualité de l'interface entre le dispositif implanté et le tissu cérébral. Pour s'affranchir de ce phénomène, la biocompatibilité des matériaux et des procédés, ainsi que les propriétés mécaniques de l'électrode doivent être pris en considération. Durant cette thèse, nous avons abordé la question en développant un procédé de fabrication simple pour réaliser des dispositifs implantables souples en parylène. Les électrodes flexibles ainsi obtenues sont totalement biocompatibles et leur compliance est adaptée à celle du tissu cérébral ce qui limite fortement la réaction inflammatoire occasionnée par les mouvements du cerveau. Après avoir optimisé le procédé de fabrication, nous avons focalisé notre étude sur les performances du dispositif et sa stabilité. L'utilisation d'une grande densité d'électrodes micrométriques, avec un diamètre de 10 à 50 µm, permet de localiser les zones d'enregistrement en rendant possible, par exemple, la conversion d'un ensemble de signaux électrophysiologiques en une commande de mouvement. En contrepartie, la réduction de la taille des électrodes conduit à une augmentation de l'impédance ce qui dégrade la qualité d'enregistrement des signaux. Ici, un polymère conducteur organique, le poly(3,4-ethylenedioxythiophene), PEDOT, a été utilisé pour améliorer les caractéristiques électriques d'enregistrement d'électrodes de petites dimensions. Le PEDOT a été déposé sur la surface des électrodes par électrochimie avec une grande reproductibilité. Des dépôts homogènes avec des conductivités électriques très élevées ont été obtenus en utilisant différents procédés électrochimiques. Grâce à l'augmentation du rapport surface/volume induit par la présence de la couche de PEDOT, une diminution significative de l'impédance de l'électrode (jusqu'à 3 ordres de grandeur) a été obtenue sur une large plage de fréquences. De tests de vieillissement thermique accéléré ont également été effectués sans influence notable sur les propriétés électriques démontrant ainsi la stabilité de la couche de PEDOT durant plusieurs mois. Les dispositifs ainsi obtenus, fabriqués en parylène avec un dépôt de PEDOT sur la surface active des électrodes, ont été testés in vitro et in vivo sur des cerveaux de souris. Un meilleur rapport signal sur bruit a été mesuré durant des enregistrements neuronaux en comparaison avec des résultats obtenus avec des électrodes commerciales. En conclusion, la technologie décrite ici, associant stabilité sur le long terme et faible impédance, a permis d'obtenir des électrodes implantables parfaitement adaptées pour le développement d'interfaces neuronales chroniques.Implantable neural prosthetics devices offer, nowadays, a promising opportunity for the restoration of lost functions in patients affected by brain or spinal cord injury, by providing the brain with a non-muscular channel able to link machines to the nervous system. The long term reliability of these devices constituted by implantable electrodes has emerged as a crucial factor in view of the application in the "brain-machine interface" domain. However, current electrodes for recording or stimulation still fail within months or even weeks. This lack of long-term reliability, mainly related to the chronic foreign body reaction, is induced, at the beginning, by insertion trauma, and then exacerbated as a result of mechanical mismatch between the electrode and the tissue during brain motion. All these inflammatory factors lead, over the time, to the encapsulation of the electrode by an insulating layer of reactive cells thus impacting the quality of the interface between the implanted device and the brain tissue. To overcome this phenomenon, both the biocompatibility of materials and processes, and the mechanical properties of the electrodes have to be considered. During this PhD, we have addressed both issues by developing a simple process to fabricate soft implantable devices fully made of parylene. The resulting flexible electrodes are fully biocompatible and more compliant with the brain tissue thus limiting the inflammatory reaction during brain motions. Once the fabrication process has been completed, our study has been focused on the device performances and stability. The use of high density micrometer electrodes with a diameter ranging from 10 to 50 µm, on one hand, provides more localized recordings and allows converting a series of electrophysiological signals into, for instance, a movement command. On the other hand, as the electrode dimensions decrease, the impedance increases affecting the quality of signal recordings. Here, an organic conductive polymer, the poly(3,4-ethylenedioxythiophene), PEDOT, has been used to improve the recording characteristics of small electrodes. PEDOT was deposited on electrode surfaces by electrochemical deposition with a high reproducibility. Homogeneous coatings with a high electrical conductivity were obtained using various electrochemical routes. Thanks to the increase of the surface to volume ratio provided by the PEDOT coating, a significant lowering of the electrode impedance (up to 3 orders of magnitude) has been obtained over a wide range of frequencies. Thermal accelerated ageing tests were also performed without any significant impact on the electrical properties demonstrating the stability of the PEDOT coatings over several months. The resulting devices, made of parylene with a PEDOT coating on the active surface of electrodes, have been tested in vitro and in vivo in mice brain. An improved signal to noise ratio during neural recording has been measured in comparison to results obtained with commercially available electrodes. In conclusion, the technology described here, combining long-term stability and low impedance, make these implantable electrodes suitable candidates for the development of chronic neural interfaces

De animais a máquinas : humanos tecnicamente melhores nos imaginários de futuro da convergência tecnológica

Dissertação (mestrado)—Universidade de Brasília, Instituto de Ciências Sociais, Departamento de Sociologia, 2020.O tema desta investigação é discutir os imaginários sociais de ciência e tecnologia que emergem a partir da área da neuroengenharia, em sua relação com a Convergência Tecnológica de quatro disciplinas: Nanotecnologia, Biotecnologia, tecnologias da Informação e tecnologias Cognitivas - neurociências- (CT-NBIC). Estas áreas desenvolvem-se e são articuladas por meio de discursos que ressaltam o aprimoramento das capacidades físicas e cognitivas dos seres humanos, com o intuito de construir uma sociedade melhor por meio do progresso científico e tecnológico, nos limites das agendas de pesquisa e desenvolvimento (P&D). Objetivos: Os objetivos nesse cenário, são discutir as implicações éticas, econômicas, políticas e sociais deste modelo de sistema sociotécnico. Nos referimos, tanto as aplicações tecnológicas, quanto as consequências das mesmas na formação dos imaginários sociais, que tipo de relações se estabelecem e como são criadas dentro desse contexto. Conclusão: Concluímos na busca por refletir criticamente sobre as propostas de aprimoramento humano mediado pela tecnologia, que surgem enquanto parte da agenda da Convergência Tecnológica NBIC. No entanto, as propostas de melhoramento humano vão muito além de uma agenda de investigação. Há todo um quadro de referências filosóficas e políticas que defendem o aprimoramento da espécie, vertentes estas que se aliam a movimentos trans-humanistas e pós- humanistas, posições que são ao mesmo tempo éticas, políticas e econômicas. A partir de nossa análise, entendemos que ciência, tecnologia e política estão articuladas, em coprodução, em relação às expectativas de futuros que são esperados ou desejados. Ainda assim, acreditamos que há um espaço de diálogo possível, a partir do qual buscamos abrir propostas para o debate público sobre questões de ciência e tecnologia relacionadas ao aprimoramento da espécie humana.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)The subject of this research is to discuss the social imaginaries of science and technology that emerge from the area of neuroengineering in relation with the Technological Convergence of four disciplines: Nanotechnology, Biotechnology, Information technologies and Cognitive technologies -neurosciences- (CT-NBIC). These areas are developed and articulated through discourses that emphasize the enhancement of human physical and cognitive capacities, the intuition it is to build a better society, through the scientific and technological progress, at the limits of the research and development (R&D) agendas. Objectives: The objective in this scenery, is to discuss the ethic, economic, politic and social implications of this model of sociotechnical system. We refer about the technological applications and the consequences of them in the formation of social imaginaries as well as the kind of social relations that are created and established in this context. Conclusion: We conclude looking for critical reflections about the proposals of human enhancement mediated by the technology. That appear as a part of the NBIC technologies agenda. Even so, the proposals of human enhancement go beyond boundaries that an investigation agenda. There is a frame of philosophical and political references that defend the enhancement of the human beings. These currents that ally to the transhumanism and posthumanism movements, positions that are ethic, politic and economic at the same time. From our analysis, we understand that science, technology and politics are articulated, are in co-production, regarding the expected and desired futures. Even so, we believe that there is a space of possible dialog, from which we look to open proposals for the public discussion on questions of science and technology related to enhancement of human beings