Fabrication and validation of an intraneural interface tailored for optic nerve stimulation

Technological progress in materials science and microengineering along with new discoveries in neuroscience have contributed to restore lost or impaired sensory functions by closely interfacing with the nervous system. Electronic devices have begun to be integrated within the body to artificially reproduce or record the electrical encoding of neural signals, the language of the nervous system. This has allowed us to restore the impaired communication between the missing or defective organ and the brain. As evidence of this, cochlear implants have returned hearing to millions of people world wide. On the other hand, there is no suitable solution yet for the 43 millions people who are currently blind. Nevertheless, several research groups and companies are trying to tackle this issue. So far, different devices have demonstrated the capability of restoring a certain degree of artificial vision, however, with limited success in delivering meaningful improvements in daily life activities. This is because, unlike hearing, vision is an extremely complex sense and requires higher stimulation resolution. Limitations of retinal prostheses have pushed further the investigation of other targets along the visual pathway, such as the optic nerve, the thalamus and the visual cortex. Among these, our group has started to explore the possibility of stimulating the optic nerve. The main advantages are the direct stimulation of the axon fibers and the access to the entire visual field with only one device. It is also interesting because it could work for those patients who are not eligible for retinal prostheses, due to severe eye trauma or retinal detachment, and it does not require optical transparency.In this thesis, we investigate stimulation strategies and materials to improve the outcome of optic nerve prostheses and make them one step closer to a viable option for blind patients. We first propose the use of machine learning algorithms to classify cortical activity upon electrical stimulation of the optic nerve. Secondly, we investigate a strategy to achieve higher spatial selectivity of the optic nerve stimulation. We design a three-dimensional (3D) multilayer concentric bipolar (CB) configuration and fabricate a modified version of the OpticSELINE. We validate the efficacy of the novel design during in-vivo experiments on rabbits and find that cortical activation is reduced when using the 3D multilayer CB electrodes compared to the classic monopolar configuration. In parallel, we explore the use of novel polymers, namely Off-Stoichiometry Thiol- Ene Epoxy (OSTE+), to design conformable neural interfaces. Their chemistry makes them a suitable candidate for easy integration in cleanroom processes and they show superior adhesion properties with respect to standard thin films currently in use. Hence, we characterise their usability as substrate and encapsulation for neural interfaces in-vitro and in-vivo. Lastly, we propose an alternative fabrication technique, ink-jet printing of platinum on flexible substrates, for neurophysiology applications. Altogether, the findings highlighted in this thesis will hopefully lead to a more in-depth investigation of the optic nerve prosthesis and can also be relevant for other applications in the field of neuroprosthetics.

Selective electrical and optical neuromodulation of the central nervous system with conformable microfabricated implants

Amélie Anne Guex

Neuroprosthetic systems are designed to interface with the nervous system, for the replacement or restoration of damaged functions in the motor and/or sensory systems. In order to have an efficient communication with the nervous tissue leading to optimized clinical outcomes, achieving neural stimulation with high selectivity is essential. This thesis aims at finding technological routes to enable spatial, structural and cell-type selective surface neuromodulation using electrical and optogenetic stimulation and to validate them in in vivo models. Thin and conformable electrode arrays enable close contact with the target tissue, thereby leading to minimal distances with the target neurons and maximal spatial selectivity. Flexible polymer technologies based on polyimide (PI) are used to design thin (< 10 ÎŒm thick) electrode arrays with small feature size (< 100 ÎŒm), resulting in miniaturized conformable arrays for surface stimulation. PEDOT conducting polymer coatings are used on the miniaturized electrical stimulation sites (100 ÎŒm diameter) to improve their charge injection properties. This implant is used for auditory brainstem stimulation in a rat model, and is shown to generate robust activation of the auditory system. Analysis of the multiunit recordings obtained from the inferior colliculus (IC), an auditory structure of the midbrain, led to the identification of different phases in the responses, with various frequency tuning properties. The stimulation configuration is shown to influence the tonotopic organisation of the frequency-tuned responses. Bipolar stimulation with small interelectrode distances (400 ÎŒm) is shown to generate responses that are more frequency-selective than with larger interelectrode distances (800 ÎŒm). The orientation of the electrode pair and the waveformof stimulation current are also shown to influence the response properties. An updated design of the clinical auditory brainstem implant(ABI) is then proposed, integrating higher electrode density and guidelines for a more tissue-conformal format. The main steps in the road towards improvement of ABI outcomes are then discussed, with proposed changes in the stimulation protocol and electrode array in parallel. Another approach to cell-specific neuromodulation is the implementation of optogenetics. This requires not only genetic engineering of the neurons but also the manufacturing of implantable light-emitting devices. Here, we introduce a fabrication process for the integration of thin (50 ÎŒm) LEDs into a polyimide-based device. A proof-of-concept in vivo study shows that stimulation of the spinal cord of a mouse model generates robust EMG responses in both legs over the course of several weeks. The walking integrity is confirmed, showing the absence of functional damages to the spinal cord. These results show that the presented LED array can provide a way of stimulating key elements of the locomotor neural circuitry, potentially leading to a greater understanding of the role of each neuronal subtypes in the spinal cord. Through the applications of ABI and spinal cord stimulation, this thesis thus highlights the importance and potential use of specifically tailored technologies enabling selective surface stimulation of the nervous system.

EPFL2017

Investigation of electrical stimulation of the optic nerve for artificial vision

Vivien Gaillet

Thanks to recent technological advances in microelectronics and bioengineering, it is now possible to restore lost or impaired sensory modalities by interfering the nervous system with elec-tronic devices and artificially reproducing the electrical encoding of the neural signals of the missing or defective sensory organs or tissues, as evidenced by the successful development of cochlear im-plants allow the restoration of hearing in deaf patients. This makes the treatment of blindness, a very impairing condition that significantly decreases the quality of life of the person it affects, a plausible possibility today, and many groups are currently attempting to apply the same principle of cochlear implants to sight restoration. So far, the preferred approach has been retinal implants due to their proximity to the defective cells, the photoreceptors, which minimizes the amount of processing of the neural signal that needs to be reproduced, and due to the reasonable number of stimulating sites that the retina can accommodate. Several devices have already demonstrated the possibility of restor-ing some degree of functional vision, albeit still very rudimentary. However, unlike hearing, vision is an extremely complex sensory modality, involving several cell types forming elaborate circuitry, which makes the advantages of retinal implants less definitive, and other alternative approaches such as op-tic nerve of cortical prosthesis still worth exploring. We believe the optic nerve stimulation is an at-tractive approach for several reasons; firstly, it does not require optical transparency. Secondly, it can address specific conditions such as severe eye trauma or retinal detachment where retinal implants cannot be employed. Finally, thanks to the organization of the optic nerve axonal fibers, it may likely result in the activation of axons originating from the same region of the visual field. This is not the case with epiretinal implants, which have been reported to stimulate undesired axons of passage in addition to the somas of their cellular targets, resulting in curved and elongated phosphenes that lim-it the implant's achievable resolution. In this thesis, we introduce a novel intraneural electrode design, the OpticSELINE, which aims at im-proving the selectivity and stability of the extra-neural cuff-electrodes previously used in optic nerve stimulation. We first characterized the device's improved mechanical and electrical properties and then proceeded to evaluate its stimulation capacity in vivo in the rabbit. In parallel to demonstrating the ability to modulate the magnitude of the cortical activation through the increase or decrease of the stimulation current, we implemented a hybrid finite element computational model to estimate the dimensions of the nerve portions activated by our electrical stimulation protocols. Using inde-pendent component analysis (ICA), we also developed a workflow that allows isolating components of the signal selectively related to a single or a pair of stimulating electrodes. We then focused on the development of new and improved algorithms to analyze the cortical activation patterns. We first developed a support machine vector (SVM)-based classifier that allowed us to accurately identify both the visual stimulus or the stimulating electrode that elicited a given cortical activation pattern amongst ten and eight total potential stimuli. Finally, we developed a regression model that also al-lowed us to accurat

EPFL2021

Selective electrical and optical neuromodulation of the central nervous system with conformable microfabricated implants

Amélie Anne Guex

EPFL2017

Investigation of electrical stimulation of the optic nerve for artificial vision

Vivien Gaillet

EPFL2021