A spinal cord neuroprosthesis for locomotor deficits due to Parkinson's disease.

People with late-stage Parkinson's disease (PD) often suffer from debilitating locomotor deficits that are resistant to currently available therapies. To alleviate these deficits, we developed a neuroprosthesis operating in closed loop that targets the dorsal root entry zones innervating lumbosacral segments to reproduce the natural spatiotemporal activation of the lumbosacral spinal cord during walking. We first developed this neuroprosthesis in a non-human primate model that replicates locomotor deficits due to PD. This neuroprosthesis not only alleviated locomotor deficits but also restored skilled walking in this model. We then implanted the neuroprosthesis in a 62-year-old male with a 30-year history of PD who presented with severe gait impairments and frequent falls that were medically refractory to currently available therapies. We found that the neuroprosthesis interacted synergistically with deep brain stimulation of the subthalamic nucleus and dopaminergic replacement therapies to alleviate asymmetry and promote longer steps, improve balance and reduce freezing of gait. This neuroprosthesis opens new perspectives to reduce the severity of locomotor deficits in people with PD.

A low-profile electromechanical packaging system for soft-to-flexible bioelectronic interfaces.

Interfacing the human body with the next generation of electronics requires technological advancement in designing and producing bioelectronic circuits. These circuits must integrate electrical functionality while simultaneously addressing limitations in mechanical compliance and dynamics, biocompatibility, and consistent, scalable manufacturing. The combination of mechanically disparate materials ranging from elastomers to inorganic crystalline semiconductors calls for modular designs with reliable and scalable electromechanical connectors. Here, we report on a novel interconnection solution for soft-to-flexible bioelectronic interfaces using a patterned and machined flexible printed circuit board, which we term FlexComb, interfaced with soft transducing systems. Using a simple assembly process, arrays of protruding "fingers" bearing individual electrical terminals are laser-machined on a standard flexible printed circuit board to create a comb-like structure, namely, the FlexComb. A matching pattern is also machined in the soft system to host and interlock electromechanically the FlexComb connections via a soft electrically conducting composite. We examine the electrical and electromechanical properties of the interconnection and demonstrate the versatility and scalability of the method through various customized submillimetric designs. In a pilot in vivo study, we validate the stability and compatibility of the FlexComb technology in a subdural electrocorticography system implanted for 6 months on the auditory cortex of a minipig. The FlexComb provides a reliable and simple technique to bond and connect soft transducing systems with flexible or rigid electronic boards, which should find many implementations in soft robotics and wearable and implantable bioelectronics.

Integration of hydrogels in microfabrication processes for bioelectronic medicine: Progress and outlook.

Recent research aiming at the development of electroceuticals for the treatment of medical conditions such as degenerative diseases, cardiac arrhythmia and chronic pain, has given rise to microfabricated implanted bioelectronic devices capable of interacting with host biological tissues in synergistic modalities. Owing to their multimodal affinity to biological tissues, hydrogels have emerged as promising interface materials for bioelectronic devices. Here, we review the state-of-the-art and forefront in the techniques used by research groups for the integration of hydrogels into the microfabrication processes of bioelectronic devices, and present the manufacturability challenges to unlock their further clinical deployment.

Epidural electrical stimulation of the cervical dorsal roots restores voluntary upper limb control in paralyzed monkeys.

Regaining arm control is a top priority for people with paralysis. Unfortunately, the complexity of the neural mechanisms underlying arm control has limited the effectiveness of neurotechnology approaches. Here, we exploited the neural function of surviving spinal circuits to restore voluntary arm and hand control in three monkeys with spinal cord injury, using spinal cord stimulation. Our neural interface leverages the functional organization of the dorsal roots to convey artificial excitation via electrical stimulation to relevant spinal segments at appropriate movement phases. Stimulation bursts targeting specific spinal segments produced sustained arm movements, enabling monkeys with arm paralysis to perform an unconstrained reach-and-grasp task. Stimulation specifically improved strength, task performances and movement quality. Electrophysiology suggested that residual descending inputs were necessary to produce coordinated movements. The efficacy and reliability of our approach hold realistic promises of clinical translation.

Chronic recording of cortical activity underlying vocalization in awake minipigs.

BACKGROUND: Investigating brain dynamics underlying vocal production in animals is a powerful way to inform on the neural bases of human speech. In particular, brain networks underlying vocal production in non-human primates show striking similarities with the human speech production network. However, despite increasing findings also in birds and more recently in rodents, the extent to which the primate vocal cortical network model generalizes to other non-primate mammals remains unclear. Especially, no domestic species has yet been proposed to investigate vocal brain activity using electrophysiological approaches. NEW METHOD: In the present study, we introduce a novel experimental paradigm to identify the cortical dynamics underlying vocal production in behaving minipigs. A key problem to chronically implant cortical probes in pigs is the presence and growth of frontal sinuses extending caudally to the parietal bone and preventing safe access to neural structures with conventional craniotomy in adult animals. RESULTS: Here we first show that implantations of soft ECoG grids can be done safely using conventional craniotomy in minipigs younger than 5 months, a period when sinuses are not yet well developed. Using wireless recordings in behaving animals, we further show activation of the motor and premotor cortex around the onset of vocal production of grunts, the most common vocalization of pigs. CONCLUSION: These results suggest that minipigs, which are very loquacious and social animals, can be a good experimental large animal model to study the cortical bases of vocal production.

Biomedical Microtechnologies Beyond Scholarly Impact.

The recent tremendous advances in medical technology at the level of academic research have set high expectations for the clinical outcomes they promise to deliver. To the demise of patient hopes, however, the more disruptive and invasive a new technology is, the bigger the gap is separating the conceptualization of a medical device and its adoption into healthcare systems. When technology breakthroughs are reported in the biomedical scientific literature, news focus typically lies on medical implications rather than engineering progress, as the former are of higher appeal to a general readership. While successful therapy and diagnostics are indeed the ultimate goals, it is of equal importance to expose the engineering thinking needed to achieve such results and, critically, identify the challenges that still lie ahead. Here, we would like to provoke thoughts on the following questions, with particular focus on microfabricated medical devices: should research advancing the maturity and reliability of medical technology benefit from higher accessibility and visibility? How can the scientific community encourage and reward academic work on the overshadowed engineering aspects that will facilitate the evolution of laboratory samples into clinical devices?

Extended Barrier Lifetime of Partially Cracked Organic/Inorganic Multilayers for Compliant Implantable Electronics.

Flexible and soft bioelectronics display conflicting demands on miniaturization, compliance, and reliability. Here, the authors investigate the design and performance of thin encapsulation multilayers against hermeticity and mechanical integrity. Partially cracked organic/inorganic multilayer coatings are demonstrated to display surprisingly year-long hermetic lifetime under demanding mechanical and environmental loading. The thin hermetic encapsulation is grown in a single process chamber as a continuous multilayer with dyads of atomic layer deposited (ALD) Al2 O3 -TiO2 and chemical vapor deposited Parylene C films with strong interlayer adhesion. Upon tensile loading, tortuous diffusion pathways defined along channel cracks in the ALD oxide films and through tough Parylene films efficiently postpone the hermeticity failure of the partially cracked coating. The authors assessed the coating performance against prolonged exposure to biomimetic physiological conditions using coated magnesium films, platinum interdigitated electrodes, and optoelectronic devices prepared on stretchable substrates. Designed extension of the lifetime preventing direct failures reduces from over 5 years yet tolerates the lifetime of 3 years even with the presence of critical damage, while others will directly fail less than two months at 37 °C. This strategy should accelerate progress on thin hermetic packaging for miniaturized and compliant implantable electronics.

MRI-Compatible and Conformal Electrocorticography Grids for Translational Research.

Intraoperative electrocorticography (ECoG) captures neural information from the surface of the cerebral cortex during surgeries such as resections for intractable epilepsy and tumors. Current clinical ECoG grids come in evenly spaced, millimeter-sized electrodes embedded in silicone rubber. Their mechanical rigidity and fixed electrode spatial resolution are common shortcomings reported by the surgical teams. Here, advances in soft neurotechnology are leveraged to manufacture conformable subdural, thin-film ECoG grids, and evaluate their suitability for translational research. Soft grids with 0.2 to 10 mm electrode pitch and diameter are embedded in 150 µm silicone membranes. The soft grids are compatible with surgical handling and can be folded to safely interface hidden cerebral surface such as the Sylvian fold in human cadaveric models. It is found that the thin-film conductor grids do not generate diagnostic-impeding imaging artefacts (<1 mm) nor adverse local heating within a standard 3T clinical magnetic resonance imaging scanner. Next, the ability of the soft grids to record subdural neural activity in minipigs acutely and two weeks postimplantation is validated. Taken together, these results suggest a promising future alternative to current stiff electrodes and may enable the future adoption of soft ECoG grids in translational research and ultimately in clinical settings.

Dimensional scaling of thin-film stimulation electrode systems in translational research.

Objective.Electrical stimulation of biological tissue is an established technique in research and clinical practice that uses implanted electrodes to deliver electrical pulses for a variety of therapies. Significant research currently explores new electrode system technologies and stimulation protocols in preclinical models, aiming at both improving the electrode performance and confirming therapeutic efficacy. Assessing the scalability of newly proposed electrode technology and their use for tissue stimulation remains, however, an open question.Approach.We propose a simplified electrical model that formalizes the dimensional scaling of stimulation electrode systems. We use established equations describing the electrode impedance, and apply them to the case of stimulation electrodes driven by a voltage-capped pulse generator.Main results.We find a hard, intrinsic upward scalability limit to the electrode radius that largely depends on the conductor technology. We finally provide a simple analytical formula predicting the maximum size of a stimulation electrode as a function of the stimulation parameters and conductor resistance.Significance.Our results highlight the importance of careful geometrical and electrical designs of electrode systems based on novel thin-film technologies and that become particularly relevant for their translational implementation with electrode geometries approaching clinical human size electrodes and interfacing with voltage-capped neurostimulation systems.

Neuroprosthetic baroreflex controls haemodynamics after spinal cord injury.

Spinal cord injury (SCI) induces haemodynamic instability that threatens survival1-3, impairs neurological recovery4,5, increases the risk of cardiovascular disease6,7, and reduces quality of life8,9. Haemodynamic instability in this context is due to the interruption of supraspinal efferent commands to sympathetic circuits located in the spinal cord10, which prevents the natural baroreflex from controlling these circuits to adjust peripheral vascular resistance. Epidural electrical stimulation (EES) of the spinal cord has been shown to compensate for interrupted supraspinal commands to motor circuits below the injury11, and restored walking after paralysis12. Here, we leveraged these concepts to develop EES protocols that restored haemodynamic stability after SCI. We established a preclinical model that enabled us to dissect the topology and dynamics of the sympathetic circuits, and to understand how EES can engage these circuits. We incorporated these spatial and temporal features into stimulation protocols to conceive a clinical-grade biomimetic haemodynamic regulator that operates in a closed loop. This 'neuroprosthetic baroreflex' controlled haemodynamics for extended periods of time in rodents, non-human primates and humans, after both acute and chronic SCI. We will now conduct clinical trials to turn the neuroprosthetic baroreflex into a commonly available therapy for people with SCI.

Recruitment of upper-limb motoneurons with epidural electrical stimulation of the cervical spinal cord.

Epidural electrical stimulation (EES) of lumbosacral sensorimotor circuits improves leg motor control in animals and humans with spinal cord injury (SCI). Upper-limb motor control involves similar circuits, located in the cervical spinal cord, suggesting that EES could also improve arm and hand movements after quadriplegia. However, the ability of cervical EES to selectively modulate specific upper-limb motor nuclei remains unclear. Here, we combined a computational model of the cervical spinal cord with experiments in macaque monkeys to explore the mechanisms of upper-limb motoneuron recruitment with EES and characterize the selectivity of cervical interfaces. We show that lateral electrodes produce a segmental recruitment of arm motoneurons mediated by the direct activation of sensory afferents, and that muscle responses to EES are modulated during movement. Intraoperative recordings suggested similar properties in humans at rest. These modelling and experimental results can be applied for the development of neurotechnologies designed for the improvement of arm and hand control in humans with quadriplegia.

A modular strategy for next-generation upper-limb sensory-motor neuroprostheses.

Neuroprosthetics is a discipline that aims at restoring lost functions to people affected by a variety of neurological disorders or neurotraumatic lesions. It combines the expertise of computer science and electrical, mechanical, and micro/nanotechnology with cellular, molecular, and systems neuroscience. Rapid breakthroughs in the field during the past decade have brought the hope that neuroprostheses can soon become a clinical reality, in particular-as we will detail in this review-for the restoration of hand functions. We argue that any neuroprosthesis relies on a set of hardware and algorithmic building elements that we call the neurotechnological modules (NTs) used for motor decoding, movement restoration, or sensory feedback. We will show how the modular approach is already present in current neuroprosthetic solutions and how we can further exploit it to imagine the next generation of neuroprosthetics for sensory-motor restoration.

Guidelines to Study and Develop Soft Electrode Systems for Neural Stimulation.

Electrical stimulation of nervous structures is a widely used experimental and clinical method to probe neural circuits, perform diagnostics, or treat neurological disorders. The recent introduction of soft materials to design electrodes that conform to and mimic neural tissue led to neural interfaces with improved functionality and biointegration. The shift from stiff to soft electrode materials requires adaptation of the models and characterization methods to understand and predict electrode performance. This guideline aims at providing (1) an overview of the most common techniques to test soft electrodes in vitro and in vivo; (2) a step-by-step design of a complete study protocol, from the lab bench to in vivo experiments; (3) a case study illustrating the characterization of soft spinal electrodes in rodents; and (4) examples of how interpreting characterization data can inform experimental decisions. Comprehensive characterization is paramount to advancing soft neurotechnology that meets the requisites for long-term functionality in vivo.

Structured nanoscale metallic glass fibres with extreme aspect ratios.

Micro- and nanoscale metallic glasses offer exciting opportunities for both fundamental research and applications in healthcare, micro-engineering, optics and electronics. The scientific and technological challenges associated with the fabrication and utilization of nanoscale metallic glasses, however, remain unresolved. Here, we present a simple and scalable approach for the fabrication of metallic glass fibres with nanoscale architectures based on their thermal co-drawing within a polymer matrix with matched rheological properties. Our method yields well-ordered and uniform metallic glasses with controllable feature sizes down to a few tens of nanometres, and aspect ratios greater than 1010. We combine fluid dynamics and advanced in situ transmission electron microscopy analysis to elucidate the interplay between fluid instability and crystallization kinetics that determines the achievable feature sizes. Our approach yields complex fibre architectures that, combined with other functional materials, enable new advanced all-in-fibre devices. We demonstrate in particular an implantable metallic glass-based fibre probe tested in vivo for a stable brain-machine interface that paves the way towards innovative high-performance and multifunctional neuro-probes.

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.

Conformable Hybrid Systems for Implantable Bioelectronic Interfaces.

Conformable bioelectronic systems are promising tools that may aid the understanding of diseases, alleviate pathological symptoms such as chronic pain, heart arrhythmia, and dysfunctions, and assist in reversing conditions such as deafness, blindness, and paralysis. Combining reduced invasiveness with advanced electronic functions, hybrid bioelectronic systems have evolved tremendously in the last decade, pushed by progress in materials science, micro- and nanofabrication, system assembly and packaging, and biomedical engineering. Hybrid integration refers here to a technological approach to embed within mechanically compliant carrier substrates electronic components and circuits prepared with traditional electronic materials. This combination leverages mechanical and electronic performance of polymer substrates and device materials, respectively, and offers many opportunities for man-made systems to communicate with the body with unmet precision. However, trade-offs between materials selection, manufacturing processes, resolution, electrical function, mechanical integrity, biointegration, and reliability should be considered. Herein, prominent trends in manufacturing conformable hybrid systems are analyzed and key design, function, and validation principles are outlined together with the remaining challenges to produce reliable conformable, hybrid bioelectronic systems.

Conformable bioelectronic interfaces: Mapping the road ahead.

Translating conformable bioelectronic interface research into clinical reality foretells a promising future for an aging society.

Selective Recruitment of Arm Motoneurons in Nonhuman Primates Using Epidural Electrical Stimulation of the Cervical Spinal Cord.

Recovery of reaching and grasping ability is the priority for people with cervical spinal cord injury (SCI). Epidural electrical stimulation (EES) has shown promising results in improving motor control after SCI in various animal models and in humans. Notably, the application of stimulation bursts with spatiotemporal sequences that reproduce the natural activation of motoneurons restored skilled leg movements in rodent and nonhuman primate models of SCI. Here, we studied whether this conceptual framework could be transferred to the design of cervical EES protocols for the recovery of reaching and grasping in nonhuman primates. We recorded muscle activity during a reaching and grasping task in a macaque monkey and found that this task involves a stereotypical spatiotemporal map of motoneuron activation. We then characterized the specificity of a spinal implant for the delivery of EES to cervical spinal segments in the same animal. Finally, we combined these results to design a simple stimulation protocol that may reproduce natural motoneuron activation and thus facilitate upper limb movements after injury.

Long-term functionality of a soft electrode array for epidural spinal cord stimulation in a minipig model.

Long-term biointegration of man-made neural interfaces is influenced by the mechanical properties of the implant materials. Substantial experimental work currently aims at replacing conventional hard implant materials with soft alternatives that can favour a lower immune response. Here we assess the performance of a soft electrode array implanted in the spinal epidural space of a minipig model for a period of 6 months. The electrode array includes platinum-silicone electrode contacts and elastic thin-film gold interconnects embedded in silicone. textbfIn-vivo electrode impedance and voltage transients were monitored over time. Following implantation, epidural stimulation produced muscle-specific evoked potentials and visible muscle contractions. Over time, postoperative and stimulation induced changes in electrode impedance were observed. Such trends provide a basis for future technological improvements aiming at ensuring the stability of soft implantable electrodes for neural interfacing.

Integration of Electrodeposited Ni-Fe in MEMS with Low-Temperature Deposition and Etch Processes.

This article presents a set of low-temperature deposition and etching processes for the integration of electrochemically deposited Ni-Fe alloys in complex magnetic microelectromechanical systems, as Ni-Fe is known to suffer from detrimental stress development when subjected to excessive thermal loads. A selective etch process is reported which enables the copper seed layer used for electrodeposition to be removed while preserving the integrity of Ni-Fe. In addition, a low temperature deposition and surface micromachining process is presented in which silicon dioxide and silicon nitride are used, respectively, as sacrificial material and structural dielectric. The sacrificial layer can be patterned and removed by wet buffered oxide etch or vapour HF etching. The reported methods limit the thermal budget and minimise the stress development in Ni-Fe. This combination of techniques represents an advance towards the reliable integration of Ni-Fe components in complex surface micromachined magnetic MEMS.