Soft, Implantable Bioelectronic Interfaces for Translational Research

The convergence of materials science, electronics, and biology, namely bioelectronic interfaces, leads novel and precise communication with biological tissue, particularly with the nervous system. However, the translation of lab‐based innovation toward clinical use calls for further advances in materials, manufacturing and characterization paradigms, and design rules. Herein, a translational framework engineered to accelerate the deployment of microfabricated interfaces for translational research is proposed and applied to the soft neurotechnology called electronic dura mater, e‐dura. Anatomy, implant function, and surgical procedure guide the system design. A high‐yield, silicone‐on‐silicon wafer process is developed to ensure reproducible characteristics of the electrodes. A biomimetic multimodal platform that replicates surgical insertion in an anatomy‐based model applies physiological movement, emulates therapeutic use of the electrodes, and enables advanced validation and rapid optimization in vitro of the implants. Functionality of scaled e‐dura is confirmed in nonhuman primates, where epidural neuromodulation of the spinal cord activates selective groups of muscles in the upper limbs with unmet precision. Performance stability is controlled over 6 weeks in vivo. The synergistic steps of design, fabrication, and biomimetic in vitro validation and in vivo evaluation in translational animal models are of general applicability and answer needs in multiple bioelectronic designs and medical technologies.

Soft microfabricated neural implants: a path towards translational implementation

Nicolas Vachicouras

Neuroprosthetics are a class of medical devices that aim to restore lost or impaired functions of the nervous system by electrical stimulation or recording of neural tissue. State of the art neural implants suffer today from a mechanical mismatch compared with the soft and curved host tissue, as they constrain mechanically the physiological motion dynamics of the central nervous system. This mismatch causes poor electrode-tissue contact, leading to unspecific stimulation or recording, as well as chronic scarring. This fundamental limitation of conventional systems can be overcome by developing soft neural interfaces, using more compliant materials, which can achieve chronic bio-integration and conform to the static and dynamic mechanics of neural tissue. The development of such soft neural interfaces requires the use of electrical conductors that can elastically deform while maintaining their electrical conductivity. The main objective of this thesis it to develop a new strategy to engineer elasticity in otherwise rigid materials by structuring them with specific patterns. This happens spontaneously at the microscale on stretchable gold films on silicone that display dense distributions of Y-shaped cracks to favor out-of-plane deformation. This work draws inspiration from these cracks by patterning Y-shaped cuts to engineer reversible elasticity in a multi-layer of metallic and plastic thin films. The geometry of these Y-shaped patterns was first optimized using finite element analysis and macroscopic models. Then, a fabrication process was developed enabling the micro-patterning of polyimide/platinum/polyimide interconnects with microscaled Y-shaped cuts (branches of dimensions âŒ15ÎŒm), which were then encapsulated in silicone. These encapsulated micro-patterned interconnects exhibit a sheet resistance of âŒ15Î©/sq., and remained conductive when elongated by up to 70%, with a resistance increase less than 2.5 times. They were also shown to reversibly stretch at 10% tensile strain for 1 million cycles. This technology allowed patterning of tracks down to 20 ÎŒm in width on a wafer-level scale. These patterned elastic films were then integrated as interconnects in neural implants, coupled with a previously described stretchable coating on the electrode sites. The main application addressed by this thesis is the auditory brainstem implant (ABI), a neuroprosthesis to stimulate the cochlear nucleus (CN) in the midbrain. Existing ABIs produce highly variable speech perception result and it is hypothesized that current ABIs are too stiff to conform to the curvature of the CN, which might lead to poor electrode contact with the neural structures. A soft human scale ABI was tested in a human cadaveric model to demonstrate that this novel electrode is robust to surgical manipulation and can easily be inserted in the brainstem using a dissolvable hydrosoluble guide. In addition, a scaled-down ABI array was tested in vivo in a mouse model and it was shown that it could reliably recruit the auditory system and remain durable for up to 4 weeks. In addition to ABIs, this technology was also validated for neural recordings at the surface of the minipig cortex, in an acute setting, as well as for chronic spinal cord stimulation in non-human primates. In the future, this technology could be used to develop personalized soft neural implants that could potentially provide a better chronic biointegration and a more robust interface with neural tissues.

EPFL2019

Electrical spinal cord stimulation protocols to regulate motor and autonomic functions in people with neurological disorders

Robin Jonathan Demesmaeker

Neurological disorders such as spinal cord injury (SCI) massively reduce independence and quality of life. Most often, the majority of the nervous system is still fully or partially spared, but dysfunctional due to aberrant or absent descending input from the brain. Neuromodulation techniques restore function by artificially engaging these neuronal circuits. Given its central position and multi- functional role, the spinal cord provides an excellent gateway for such therapies.Epidural Electrical Stimulation (EES) of the spinal cord has been put forward as a potential therapy to restore motor and autonomic function after SCI. Throughout the last decade, our laboratory developed the concept of biomimetic EES. Spatiotemporal stimulation parameters are optimized to re-establish the natural dynamics of the underlying spinal circuitry. Strong evidence in rodent and non- human primate models suggests that biomimetic EES could promote locomotion and haemodynamic stability after severe SCI, leading to a push for rapid clinical translation of this potentially game-changing therapy. This clinical translation is the pivot of my thesis.The first part focuses on the recovery of leg motor control after SCI. The results of a first-in-human clinical trial in 9 participants with chronic SCI are presented. We developed a set of targeted neurotechnologies that include a new epidurally implanted electrode array, real-time communication and tailormade software systems that enable the precise delivery of biomimetic EES. We demon- strate that biomimetic EES can be optimized to immediately restore a vast number of leg motor functions such as walking and cycling, as well as trunk posture. Furthermore, after 5 months of intensive EES-enabled volitional training, participants did not only all improve their motor performance while using EES, they moreover regained volitional control over previously paralyzed muscles. This neuro- logical recovery correlated with a reduced metabolic activity in the spinal cord, suggesting spinal remodeling. A systematic pre-clinical approach identified a specific neuronal population mediating these effects.The second part of my thesis considers another critically important body function: haemodynamic management. Orthostatic hypo- tension is a major health issue after severe SCI and stems from a disconnection between the vasomotor regulatory centres in the brainstem and the sympathetic circuitry that adjusts peripheral vascular resistance. Preclinical work in rodents showed that EES ap- plied to the low-thoracic spinal cord could restore haemodynamic stability after SCI. On the path towards clinical translation, we implemented closed-loop control of EES in a non-human primate model of SCI to maintain haemodynamic stability during orthostatic challenge. I moreover present a case-study that demonstrates the transferability of thoracic EES to improve haemodynamic manage- ment in a patient with Multiple System Atrophy (MSA). A marked reduction of orthostatic hypotension led to a clinically relevant decrease in fainting episodes and considerably improved quality of life.My thesis demonstrates the prosthetic and therapeutic effects of biomimetic EES and highlights its ability to immediately restore body functions and boost neurological recovery after SCI and in MSA. These results strengthen the belief that EES holds the potential to evolve into a relevant and efficient therapeutic intervention in a plentitude of neurological disorders.

EPFL2021

Cortico-reticulo-spinal circuits mediate functional recovery after spinal cord contusion

Léonie Asboth

After a spinal cord injury (SCI), only half of affected individuals regain voluntary control of leg movements below the level of the lesion. Anatomical, electrophysiological and imaging data revealed that even the most severe forms of SCI usually spare a small bridge of tissue in the surrounding of the lesion cavity. These bridges contain residual fibers from brain projections that maintain a physical connection with the lumbar spinal cord, where the circuits coordinating leg movements reside. However, without therapeutic interventions, these spared fibers will fail to conduct nervous information from brain centers to the spinal circuits below injury, leading to permanent paralysis. It is accepted that spontaneous regeneration of lesioned fibers is limited in the adult nervous system, but hope for motor recovery lies in the capacity of the spared neural motor network to readapt and find compensational routes. In the past, a neuroprosthetic rehabilitation strategy combining electrochemical neuromodulation of the spinal cord during robot-assisted overground locomotion was developed for rats to restore volitional control of the paralyzed legs. Such rehabilitation platforms was developed for rats, enabling large-scale studies prior to pre-clinical trials in non-human primates. However, most innovative tools for the manipulation of specific populations of neurons are currently designed for mice, and these techniques are essential to establish causality between the anatomical reorganization and the observed functional recovery. In the first part of this thesis, we developed a robotic interface with end-effector modules that can be rapidly exchanged between experiments with rats or mice. The functionalities of the robot are tailored to the size and weight of the animal, to the personalized need of assistance and to the type of performed task. Using this platform, the next part of the thesis uncovers the mechanisms enabling motor recovery after a clinically relevant injury model â a severe spinal cord contusion. Such injury leads to permanent leg motor deficits with very little spontaneous recovery. Similar to humans, the modelled contusion injury induce highly variable white matter damage with undefined neural pathway sparing. For the first time, we show that the rehabilitation strategy enabled rats to regain supraspinal control of leg movements that persisted without any neuromodulation even during unpracticed motor tasks. We then investigated the reorganization of the spared circuitry that mediated this functional recovery after contusion. Despite interruption of direct corticospinal projections, we showed that the motor cortex regained adaptive control over the paralyzed legs during neuromodulation of lumbar circuits. We found that the cortical command was relayed through spared glutamatergic projection neurons in the reticular formation. Indeed, due to the distributed spatial topography of reticulospinal projections, the contusion systematically spares a subset of these projections. Extensive training promoted plasticity of the identified cortico-reticulo-spinal pathway mediating a motor cortex dependent recovery of voluntary leg movements. As the anatomy and function of reticulospinal pathways are well-conserved across mammals, this pathway may be recruited by similar therapeutic interventions to improve recovery in humans.

EPFL2017