Abstract:We introduce a new class of neural implants with the topology and compliance of dura mater, the protective membrane of the brain and spinal cord. These neural interfaces, which we called e-dura, achieve chronic bio-integration within the subdural space where they conform to the statics and dynamics of neural tissue. e-dura embeds interconnects, electrodes and chemotrodes that sustain millions of mechanical stretch cycles, electrical stimulation pulses, and chemical injections. These integrated modalities enable multiple neuroprosthetic applications. e-dura extracted cortical states in freely behaving animals for brain machine interface, and delivered electrochemical spinal neuromodulation that restored locomotion after paralyzing spinal cord injury. e-dura offers a novel platform for chronic multimodal neural interfaces in basic research and neuroprosthetics.3 Neuroprosthetic medicine is improving the lives of countless individuals. Cochlear implants restore hearing in deaf children, deep brain stimulation alleviates Parkinsonian symptoms, and spinal cord neuromodulation attenuates chronic neuropathic pain (1). These interventions rely on implants developed in the 1980s (2, 3). Since then, advances in electroceutical, pharmaceutical, and more recently optogenetic treatments triggered development of myriad neural interfaces that combine multiple modalities (4-9). However, the conversion of these sophisticated technologies into chronic implants mediating long-lasting functional benefits has yet to be achieved. A recurring challenge restricting chronic bio-integration is the substantial biomechanical mismatch between implants and neural tissues (10-13). Here, we introduce a new class of soft multimodal neural interfaces that achieve chronic bio-integration, and we demonstrate their long-term efficacy in clinically relevant applications. e-dura fabrication. We designed and engineered soft interfaces that mimic the topology and mechanical behavior of the dura mater (Fig. 1A-B). The implant, which we called electronic dura mater or e-dura, integrates a transparent silicone substrate (120µm in thickness), stretchable gold interconnects (35nm in thickness), soft electrodes coated with a novel platinum-silicone composite (300µm in diameter), and a compliant fluidic microchannel (100µm x 50µm in crosssection) (Fig. 1C-D, fig. S1-S2-S3). The interconnects and electrodes transmit electrical excitation and transfer electrophysiological signals.The microfluidic channel, termed chemotrode (14), delivers drugs locally (Fig. 1C, fig. S3). Microcracks in the gold interconnects (15) and the newly developed soft platinum-silicone composite electrodes confer exceptional stretchability to the entire implant (Fig. 1B, Movie S1). The patterning techniques of metallization and microfluidics support rapid manufacturing of customized neuroprostheses.4 e-dura implantation. Most implants used experimentally or clinically to assess and treat neurological disorders are placed above the dura mater (3,(16)(17)(18). The compliance of e-...

Hand loss is a highly disabling event that markedly affects the quality of life. To achieve a close to natural replacement for the lost hand, the user should be provided with the rich sensations that we naturally perceive when grasping or manipulating an object. Ideal bidirectional hand prostheses should involve both a reliable decoding of the user's intentions and the delivery of nearly "natural" sensory feedback through remnant afferent pathways, simultaneously and in real time. However, current hand prostheses fail to achieve these requirements, particularly because they lack any sensory feedback. We show that by stimulating the median and ulnar nerve fascicles using transversal multichannel intrafascicular electrodes, according to the information provided by the artificial sensors from a hand prosthesis, physiologically appropriate (near-natural) sensory information can be provided to an amputee during the real-time decoding of different grasping tasks to control a dexterous hand prosthesis. This feedback enabled the participant to effectively modulate the grasping force of the prosthesis with no visual or auditory feedback. Three different force levels were distinguished and consistently used by the subject. The results also demonstrate that a high complexity of perception can be obtained, allowing the subject to identify the stiffness and shape of three different objects by exploiting different characteristics of the elicited sensations. This approach could improve the efficacy and "life-like" quality of hand prostheses, resulting in a keystone strategy for the near-natural replacement of missing hands.

Regaining Limb Movement Despite many years of intensive research, there is still an urgent need for novel treatments to help patients restore motor function after spinal cord injuries. van den Brand et al. (p. 1182 ) produced left and right hemisections at different levels of the rat thoracic spinal cord to cause complete hind limb paralysis mimicking the situation in humans with spinal cord injury. Systemic application of pharmacological agents, combined with a multisystem rehabilitation program including a robotic postural neuroprosthesis, restored voluntary movements of both hind limbs.

Considerable scientific and technological efforts have been devoted to develop neuroprostheses and hybrid bionic systems that link the human nervous system with electronic or robotic prostheses, with the main aim of restoring motor and sensory functions in disabled patients. A number of neuroprostheses use interfaces with peripheral nerves or muscles for neuromuscular stimulation and signal recording. Herein, we provide a critical overview of the peripheral interfaces available and trace their use from research to clinical application in controlling artificial and robotic prostheses. The first section reviews the different types of non-invasive and invasive electrodes, which include surface and muscular electrodes that can record EMG signals from and stimulate the underlying or implanted muscles. Extraneural electrodes, such as cuff and epineurial electrodes, provide simultaneous interface with many axons in the nerve, whereas intrafascicular, penetrating, and regenerative electrodes may contact small groups of axons within a nerve fascicle. Biological, technological, and material science issues are also reviewed relative to the problems of electrode design and tissue injury. The last section reviews different strategies for the use of information recorded from peripheral interfaces and the current state of control neuroprostheses and hybrid bionic systems.

Spinal cord injury disrupts the communication between the brain and the spinal circuits that orchestrate movement. To bypass the lesion, brain–computer interfaces1–3 have directly linked cortical activity to electrical stimulation of muscles, which have restored grasping abilities after hand paralysis1,4. Theoretically, this strategy could also restore control over leg muscle activity for walking5. However, replicating the complex sequence of individual muscle activation patterns underlying natural and adaptive locomotor movements poses formidable conceptual and technological challenges6,7. Recently, we showed in rats that epidural electrical stimulation of the lumbar spinal cord can reproduce the natural activation of synergistic muscle groups producing locomotion8–10. Here, we interfaced leg motor cortex activity with epidural electrical stimulation protocols to establish a brain–spinal interface that alleviated gait deficits after a spinal cord injury in nonhuman primates. Rhesus monkeys were implanted with an intracortical microelectrode array into the leg area of motor cortex; and a spinal cord stimulation system composed of a spatially selective epidural implant and a pulse generator with real-time triggering capabilities. We designed and implemented wireless control systems that linked online neural decoding of extension and flexion motor states with stimulation protocols promoting these movements. These systems allowed the monkeys to behave freely without any restrictions or constraining tethered electronics. After validation of the brain–spinal interface in intact monkeys, we performed a unilateral corticospinal tract lesion at the thoracic level. As early as six days post-injury and without prior training of the monkeys, the brain–spinal interface restored weight-bearing locomotion of the paralyzed leg on a treadmill and overground. The implantable components integrated in the brain–spinal interface have all been approved for investigational applications in similar human research, suggesting a practical translational pathway for proof-of-concept studies in people with spinal cord injury.

Epidural electrical stimulation (EES) of lumbosacral segments can restore a range of movements after spinal cord injury. However, the mechanisms and neural structures through which EES facilitates movement execution remain unclear. Here, we designed a computational model and performed in vivo experiments to investigate the type of fibers, neurons, and circuits recruited in response to EES. We first developed a realistic finite element computer model of rat lumbosacral segments to identify the currents generated by EES. To evaluate the impact of these currents on sensorimotor circuits, we coupled this model with an anatomically realistic axon-cable model of motoneurons, interneurons, and myelinated afferent fibers for antagonistic ankle muscles. Comparisons between computer simulations and experiments revealed the ability of the model to predict EES-evoked motor responses over multiple intensities and locations. Analysis of the recruited neural structures revealed the lack of direct influence of EES on motoneurons and interneurons. Simulations and pharmacological experiments demonstrated that EES engages spinal circuits trans-synaptically through the recruitment of myelinated afferent fibers. The model also predicted the capacity of spatially distinct EES to modulate side-specific limb movements and, to a lesser extent, extension versus flexion. These predictions were confirmed during standing and walking enabled by EES in spinal rats. These combined results provide a mechanistic framework for the design of spinal neuroprosthetic systems to improve standing and walking after neurological disorders.

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Highlights d Biomimetic hybrid sensory encodings are perceived as highly natural d Biomimetic hybrid sensory encodings restore rich tactile sensitivity d Biomimetic hybrid sensory encodings improve manual dexterity and accuracy d Biomimetic hybrid sensory encodings enhance prosthesis embodiment