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

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.

Electronic dura mater soft, multimodal neural interfaces

Arthur Edouard Hirsch

Neuroprosthetic devices are engineered to study, support or replace impaired functions of the nervous system. The neural interface is an essential element of neuroprosthetic systems as it allows for transduction of signals and stimuli of desired functions (recording, stimulation, neuromodulation). A persistent challenge for translating neuroprosthetics from the laboratory to the clinic is the lack of long-term biointegration of neural interfaces. This thesis aims at improving biointegration of neural interfaces by reducing the mechanical mismatch between implant and neural tissue. In this thesis, the design, fabrication and characterization of soft surface neural interfaces is described. These soft neural interfaces, termed electronic dura mater or e-dura, were designed to mimic the mechanical properties of dura mater. In contrast with conventional neural technologies, e-dura neural interfaces were made of soft and compliant materials. They conform to the circumvolutions of the brain and spinal cord and follow their dynamic deformation without damaging the surrounding neural tissues. These soft multimodal neural interfaces were fabricated on silicone substrates using techniques imported from the microfabrication industry and incorporate compliant electrodes, stretchable electrical interconnects and a micro-catheter for drug delivery. Evaluation of the e-dura biointegration with spinal tissues demonstrated reduced foreign body reaction, compared to stiff polyimide based implants. Additionally, mechanical tests on an in-vitro spinal surrogate provided insights on the complex biomechanical coupling between implants and neural tissue. E-dura interfaces, implanted in rodents, maintained their functionality over extended periods and provided high-resolution neuronal recordings and concurrent delivery of electrical and chemical neuromodulation. Eventually, the use of gallium thin films was explored to create highly conductive and stretchable interconnects for integration of active electronic components in e-dura neural interfaces.

EPFL2018

Soft multimodal neural interfaces for unravelling sensory neurological circuits

Frédéric Pierre Gérald Michoud

Diseases or injuries affecting the nervous system can dramatically disrupt the quality of life. Despite extensive efforts towards treating dysfunctional nervous systems, the pharmacological and electrical approaches generally involved lack the temporal and spatial resolutions needed to selectively modulate neural activity. The somatosensory system intertwines numerous neural populations with distinct functionalities, whose specific neuromodulation would be beneficial for the alleviation of chronic pain and the restoration of locomotion after spinal cord injury. This thesis aims to develop a new generation of electrical and optical neural interfaces to selectively parse the somatosensory system. At the peripheral nerve level, we proposed an optical cuff and a wireless optoelectronic system to deliver epineural optogenetic stimulations in freely-behaving mice. The former consists of a soft elastomeric cuff wrapped around the sciatic nerve and integrated into a thin optic fiber. We demonstrated consistent orderly recruitment of motor units with optical stimulations in Thy1::ChR2 mice. This optocuff represents a simple, yet efficient, solution to probe the peripheral nervous system using optogenetics. However, untethered experimentation offers more versatility for fine neuromodulation applications. Within this framework, we developed a system comprising an ultra-miniaturized wireless stimulator and a soft circumneural ÎŒ-LED array to deliver optogenetic stimulations to the sciatic nerve. This optoelectronic implant conformed to the nerveâs morphology and complied with its dynamic motion. We demonstrated the systemâs efficacy via optogenetic activation of nociceptors in TRPV1::ChR2 mice. Both the optocuff and the wireless optoelectronic system exhibited seamless bio-integration after chronic implantation, thus highlighting the benefits of soft neurotechnology for interfacing with peripheral nerves. At the spinal level, we introduced a transversal electrode array for multipolar epidural stimulation of the spinal cord. The silicone materials used for its fabrication conferred this implant with mechanical properties matching the dura mater, allowing for remarkable biocompatibility following long-term implantation. Based on the spinal cord anatomy, this implant displayed a wide distribution of neural electrodes at a single spinal level, which enabled selective recruit- ment of posterior spinal roots. This novel paradigm was implemented to a spatio-temporal stimulation protocol and demonstrated potential in restoring locomotion after spinal cord injury. Finally, we reported a soft ÎŒ-LED array to deliver optogenetic stimulations in deep spinal structures. Insertion of this thin (< 100 ÎŒm) optoelectronic implant in the mouse epidural space did not provoke tissue damages while maintaining its functionality with normal dynamic motion. As a proof-of-principle, we showed concomitant electromyographic activity with epidural optical stimulations in Thy1::ChR2 mice. This premise offers a large range of opportunities to probe the spinal circuits involved in sensory processing and locomotion. In conclusion, these selective neural interfaces are proposed as innovative tools to unravel peripheral and spinal neural circuits. This venue will support the development of relevant clinical treatments for tackling dysfunctional neural systems. Eventually, these implant concepts pave the way for the translation of fine neuromodulation therapies in humans.

EPFL2019

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

Eleonora Borda

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.

EPFL2022