Development of a Transient Neural Interface for Minimally Invasive Recording and Stimulation

Transient electronics enabling devices to safely disappear in the environment can be applied not only in green electronics, but also in bioelectronic medicine. Neural implants able to degrade harmlessly inside the body eliminate the need for removal surgery, allow for safe tissue remodelling, and potentially reduce inflammation responses and the chronic adverse reactions hindering device functionality and putting patients' health at risk. Sadly, current transient neurotechnology can be used only for very short-term applications. Fast degrading metals generally used to build these interfaces allow in fact for operations rarely longer than a few days, strongly limiting the available time window for collecting information or for a therapy to be finished.To solve this problem, we propose a transient, all-polymeric neural interface able to work for longer time scales. This would enable new applications of transient neurotechnology, such as recording of brain activity for a prolonged and more useful period of time before resection of epilepsy foci or tumours. The device consists of a polycaprolactone (PCL) scaffold with patterned poly 3,4-ethylene dioxythiophene : polystyrene sulfonate (PEDOT:PSS) traces and electrodes. In vivo neural recording demonstrated low noise levels for twelve weeks and histological analysis highlighted the cellular infiltration inside the PCL scaffold over time, hinting to potential tissue remodelling processes, which would not occur with a non-degradable device. To increase the device potential for a clinical translation, a minimally invasive procedure for its implantation has been proposed. The blood vasculature supplying the brain and nerves can be used as an access route to the neural tissue, offering a close enough location without direct damage to the tissue. By re-shaping the all-polymeric transient neural probe using a stent-inspired design, the new interface can be navigated through a 5Fr catheter and deployed inside 2 mm-diameter channels. Characterization showed promising electrodes endurance to pulsatile flow and prolonged stimulation, together with a good safety profile. This device can be used for neural recording or stimulation from within a blood vessel, for either central or peripheral nervous system. By simplifying the implantation procedure of the neural interface and maintaining its transiency, physicians and patients could feel more confident in applying innovative neurotechnology-based treatments, widening for example the access to deep brain stimulation therapy. To enable crossing of complex vasculature without wall ruptures caused by current manual push of guidewires, a new navigation paradigm for endovascular devices has been designed and tested on thin polyimide strips. A physiological pulsatile flow can propel these probes, even at curvatures as high as 0.25 mm-1, and low amplitude magnetic fields can steer their direction. Electrodes and sensors for temperature and flow can be embedded onto these micro-probes, for unprecedented local interrogation of deep vasculature regions. In conclusion, this thesis introduces new neural interfaces in the field of minimally invasive neurotechnology, reducing adverse effects and complications of non-degradable implants and open surgery. These devices and their concepts have the potential one day to be new tools of the bioelectronic medicine toolbox, contributing to the advancement of innovative treatments for neurodegenerative disorders.

Methods for acute and long-term imaging of the ventral nerve cord in behaving adult Drosophila

Laura Joan Hermans

Understanding how neural circuits remodel and adapt to animal behavior is a central theme in the field of Neuroscience. One strategy to reach this goal is to repeatedly record the same animal's neural circuits and observe how they adapt when facing different challenges. Research has primarily focused on identifying neural circuits and connectivity maps within the brains of model organisms. Nevertheless, it has become evident that functional recordings are essential to have a complete understanding of how neural circuits generate behaviors. Numerous techniques have been introduced to record activity from brain circuits in model animals spanning from monkeys to insects. However, imaging the spinal cord in mammals or the ventral nerve cord in insects remains an open challenge due to the complexity of obtaining optical access without impacting the animal's behavior and damaging neural tissues. As a result, we have very limited information on how neural circuits in the spinal cord generate behaviors and how they adapt to different experiences such as injury or aging. Drosophila is a perfect model organism for carrying out this line of research thanks to its small size, genetically tractable nervous system, and behavioral diversity. The results are relevant to human physiology and behavior as many mechanisms have homologs in mammals. What is missing is a technological advancement that allows recording of behavior, structural changes in the circuits, and spatiotemporal dynamics of neural activity on the same animal.This thesis addresses this gap and introduces two novel methods for in vivo functional recordings of the fly's ventral nerve cord (VNC). The first one gains short-term access to the fly's VNC using a novel dissection preparation. The second one enables long-term functional recordings of the fly's VNC thanks to a toolkit combining four microengineered devices: a surgical arm, a V-shape implant, an optically transparent and numbered window and a remounting stage. The toolkit is suitable for both male and female flies and provides optical access to the VNC for at least one month. Additionally, the long-term toolkit does not impact flies' behaviors compared to intact flies and can be used to image both sparse and large populations of neural activity in flies' cervical connective and VNC. The toolkit was tested in two proof-of-concept (POC) applications. In the first POC, the toolkit monitored the degradation of sensory neurons in the VNC over weeks following limb amputation. In the second POC, the toolkit monitored global changes in neural dynamics following ingestion of a high-concentration caffeine solution. In conclusion, this thesis introduces new techniques for functional recordings of the fly's cervical connective and VNC over short and long time scales. They enable optical access to the fly's cervical connective that can be leveraged to study the content of information transmitted between the brain and the VNC while the fly is behaving. The two POCs demonstrate that the novel technology is ideally suited for long-term experiments and could be applied to a wide range of studies. For instance, the toolkit could be used to investigate how behaviors are encoded in the fly's VNC and how they adapt over time to experiences such as disease, aging, drug intake and learning.

EPFL2022

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

Remotely Powered Wireless Cortical Implants for Brain-Machine Interfaces

Kanber Mithat Silay

Brain-machine interfaces hold promise for restoring basic functions such as movement or speech for severely disabled patients, as well as for controlling neuroprosthetic devices for amputees. One of the major challenges of clinically viable neuroprostheses for chronic use is the implementation of fully implantable recording devices for stable, long-term recordings over large populations of neurons. Recent progress in the microelectronics and MEMS technologies has enabled miniaturization of microelectrode arrays which can be used for recording the neural activity of the brain and for stimulating the neurons. Nevertheless, the demanding requirements of fully implantable recording devices necessitate the incorporation of other active components with the microelectrodes. The presence of the active components in the implant requires power to be delivered to the device. Transcutaneous wires are commonly used for this purpose as well as for communication with the outside world. However, these wires pose the risk of infection to the patient. Another common method of powering is to utilize batteries in the implant. Nevertheless, this method is not desirable as the batteries have to be replaced at the end of their lifetime with a surgical procedure. This thesis presents the development of a remotely powered wireless cortical neural interface system for brain-machine interface applications. In the scope of this work, firstly, the requirements and specifications of the system are analyzed to examine the limits of operation. In addition, the thermal impact of cortical implant operation in the head is investigated to determine the maximum allowable power consumption in the implant. In order to supply power to the active components in the cortical implant, a closed-loop inductive remote powering link operating from a single external battery is implemented. The closed-loop operation enables adaptive delivery of power depending on the implant activity. For improving the power efficiency of the link, a discrete optimization algorithm is developed to design the geometry of the power transmission coils. In addition, application specific integrated circuits are designed to enhance the overall performance of the system and to decrease the footprint of the implant electronics. Moreover, wireless data communication for cortical implants is discussed and a solution for coexistence of the power and data links is presented. For implanting the cortical recording device into the body, a two-body packaging topology is proposed to position the implant inside the cranial bone. With this topology, the performance of the cortical neural interface is significantly improved. The fabricated cortical implants with the two-body package are characterized in air and in vitro. The power transfer efficiency of the closed-loop remote powering link operating from a single supply is measured to be 10.6% in vitro for 10 mW power delivered to the implant load. Finally, the operation of the implant in vitro is validated for over five weeks.

EPFL2012

Methods for acute and long-term imaging of the ventral nerve cord in behaving adult Drosophila

Laura Joan Hermans

EPFL2022

Remotely Powered Wireless Cortical Implants for Brain-Machine Interfaces

Kanber Mithat Silay

EPFL2012

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

Eleonora Borda

EPFL2022