Doping-induced assembly interface for noninvasive in vivo local and systemic immunomodulation.

Peripheral neural interfaces, potent in modulating local and systemic immune responses for disease treatment, face significant challenges due to the peripheral nerves' broad distribution in tissues like the fascia, periosteum, and skin. The incongruity between static electronic components and the dynamic, complex organization of the peripheral nervous system often leads to interface failure, stalling circuit research and clinical applications. To overcome these, we developed a self-assembling, tissue-adaptive electrode composed of a single-component cocktail nanosheet colloid, including dopants, conducting polymers, stabilizers, and an MXene catalyst. Delivered via a jet injector to designated nerve terminals, this assembly utilizes reactive oxygen species to catalytically dope poly (3,4-ethylenedioxythiophene), enhancing π-π interactions between nanosheets, and yielding a conductive, biodegradable interface. This interface effectively regulates local immune activity and promotes sensory and motor nerve functional restoration in nerve-injured mice, while engaging the vagal-adrenal axis in freely moving mice, eliciting catecholamine neurotransmitter release, and suppressing systemic cytokine storms. This innovative strategy specifically targets nerve substructures, bolstering local and systemic immune modulation, and paving the way for the development of self-adaptive dynamic neural interfaces.

Prevention of the foreign body response to implantable medical devices by inflammasome inhibition.

SignificanceImplantable electronic medical devices (IEMDs) are used for some clinical applications, representing an exciting prospect for the transformative treatment of intractable conditions such Parkinson's disease, deafness, and paralysis. The use of IEMDs is limited at the moment because, over time, a foreign body reaction (FBR) develops at the device-neural interface such that ultimately the IEMD fails and needs to be removed. Here, we show that macrophage nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activity drives the FBR in a nerve injury model yet integration of an NLRP3 inhibitor into the device prevents FBR while allowing full healing of damaged neural tissue to occur.

Injectable Fluorescent Neural Interfaces for Cell-Specific Stimulating and Imaging.

Building on current explorations in chronic optical neural interfaces, it is essential to address the risk of photothermal damage in traditional optogenetics. By focusing on calcium fluorescence for imaging rather than stimulation, injectable fluorescent neural interfaces significantly minimize photothermal damage and improve the accuracy of neuronal imaging. Key advancements including the use of injectable microelectronics for targeted electrical stimulation and their integration with cell-specific genetically encoded calcium indicators have been discussed. These injectable electronics that allow for post-treatment retrieval offer a minimally invasive solution, enhancing both usability and reliability. Furthermore, the integration of genetically encoded fluorescent calcium indicators with injectable bioelectronics enables precise neuronal recording and imaging of individual neurons. This shift not only minimizes risks such as photothermal conversion but also boosts safety, specificity, and effectiveness of neural imaging. Embracing these advancements represents a significant leap forward in biomedical engineering and neuroscience, paving the way for advanced brain-machine interfaces.

Stretchable Tissue-Like Gold Nanowire Composites with Long-Term Stability for Neural Interfaces.

Soft and stretchable nanocomposites can match the mechanical properties of neural tissue, thereby minimizing foreign body reactions to provide optimal stimulation and recording specificity. Soft materials for neural interfaces should simultaneously fulfill a wide range of requirements, including low Young's modulus (<<1 MPa), stretchability (≥30%), high conductivity (>> 1000 S cm-1), biocompatibility, and chronic stability (>> 1 year). Current nanocomposites do not fulfill the above requirements, in particular not the combination of softness and high conductivity. Here, this challenge is addressed by developing a scalable and robust synthesis route based on polymeric reducing agents for smooth, high-aspect ratio gold nanowires (AuNWs) of controllable dimensions with excellent biocompatibility. AuNW-silicone composites show outstanding performance with nerve-like softness (250 kPa), high conductivity (16 000 S cm-1), and reversible stretchability. Soft multielectrode cuffs based on the composite achieve selective functional stimulation, recordings of sensory stimuli in rat sciatic nerves, and show an accelerated lifetime stability of >3 years. The scalable synthesis method provides a chemically stable alternative to the widely used AgNWs, thereby enabling new applications within electronics, biomedical devices, and electrochemistry.

Effects of Micromachining on Anti-oxidant Elution from a Mechanically-Adaptive Polymer.

Intracortical microelectrodes (IMEs) can be used to restore motor and sensory function as a part of brain-computer interfaces in individuals with neuromusculoskeletal disorders. However, the neuroinflammatory response to IMEs can result in their premature failure, leading to reduced therapeutic efficacy. Mechanically-adaptive, resveratrol-eluting (MARE) neural probes target two mechanisms believed to contribute to the neuroinflammatory response by reducing the mechanical mismatch between the brain tissue and device, as well as locally delivering an antioxidant therapeutic. To create the mechanically-adaptive substrate, a dispersion, casting, and evaporation method is used, followed by a microfabrication process to integrate functional recording electrodes on the material. Resveratrol release experiments were completed to generate a resveratrol release profile and demonstrated that the MARE probes are capable of long-term controlled release. Additionally, our results showed that resveratrol can be degraded by laser-micromachining, an important consideration for future device fabrication. Finally, the electrodes were shown to have a suitable impedance for single-unit neural recording and could record single units in vivo.

Miniaturized Electrochemical Sensing Platforms for Quantitative Monitoring of Glutamate Dynamics in the Central Nervous System.

Glutamate is one of the most important excitatory neurotransmitters within the mammalian central nervous system. The role of glutamate in regulating neural network signaling transmission through both synaptic and extra-synaptic paths highlights the importance of the real-time and continuous monitoring of its concentration and dynamics in living organisms. Progresses in multidisciplinary research have promoted the development of electrochemical glutamate sensors through the co-design of materials, interfaces, electronic devices, and integrated systems. This review summarizes recent works reporting various electrochemical sensor designs and their applicability as miniaturized neural probes to in vivo sensing within biological environments. We start with an overview of the role and physiological significance of glutamate, the metabolic routes, and its presence in various bodily fluids. Next, we discuss the design principles, commonly employed validation models/protocols, and successful demonstrations of multifunctional, compact, and bio-integrated devices in animal models. The final section provides an outlook on the development of the next generation glutamate sensors for neuroscience and neuroengineering, with the aim of offering practical guidance for future research.

Reading and Modulating Cortical ß Bursts from Motor Unit Spiking Activity.

ß Oscillations (13-30 Hz) are ubiquitous in the human motor nervous system. Yet, their origins and roles are unknown. Traditionally, ß activity has been treated as a stationary signal. However, recent studies observed that cortical ß occurs in "bursting events," which are transmitted to muscles. This short-lived nature of ß events makes it possible to study the main mechanism of ß activity found in the muscles in relation to cortical ß. Here, we assessed whether muscle ß activity mainly results from cortical projections. We ran two experiments in healthy humans of both sexes (N = 15 and N = 13, respectively) to characterize ß activity at the cortical and motor unit (MU) levels during isometric contractions of the tibialis anterior muscle. We found that ß rhythms observed at the cortical and MU levels are indeed in bursts. These bursts appeared to be time-locked and had comparable average durations (40-80 ms) and rates (approximately three to four bursts per second). To further confirm that cortical and MU ß have the same source, we used a novel operant conditioning framework to allow subjects to volitionally modulate MU ß. We showed that volitional modulation of ß activity at the MU level was possible with minimal subject learning and was paralleled by similar changes in cortical ß activity. These results support the hypothesis that MU ß mainly results from cortical projections. Moreover, they demonstrate the possibility to decode cortical ß activity from MU recordings, with a potential translation to future neural interfaces that use peripheral information to identify and modulate activity in the central nervous system.SIGNIFICANCE STATEMENT We show for the first time that ß activity in motor unit (MU) populations occurs in bursting events. These bursts observed in the output of the spinal cord appear to be time-locked and share similar characteristics of ß activity at the cortical level, such as the duration and rate at which they occur. Moreover, when subjects were exposed to a novel operant conditioning paradigm and modulated MU ß activity, cortical ß activity changed in a similar way as peripheral ß. These results provide evidence for a strong correspondence between cortical and peripheral ß activity, demonstrating the cortical origin of peripheral ß and opening the pathway for a new generation of neural interfaces.

Frequency Shapes the Quality of Tactile Percepts Evoked through Electrical Stimulation of the Nerves.

Electrical stimulation of the peripheral nerves of human participants provides a unique opportunity to study the neural determinants of perceptual quality using a causal manipulation. A major challenge in the study of neural coding of touch has been to isolate the role of spike timing-at the scale of milliseconds or tens of milliseconds-in shaping the sensory experience. In the present study, we address this question by systematically varying the pulse frequency (PF) of electrical stimulation pulse trains delivered to the peripheral nerves of seven participants with upper and lower extremity limb loss via chronically implanted neural interfaces. We find that increases in PF lead to systematic increases in perceived frequency, up to ∼50 Hz, at which point further changes in PF have little to no impact on sensory quality. Above this transition frequency, ratings of perceived frequency level off, the ability to discriminate changes in PF is abolished, and verbal descriptors selected to characterize the sensation change abruptly. We conclude that sensation quality is shaped by temporal patterns of neural activation, even if these patterns are imposed on a fixed neural population, but this temporal patterning can only be resolved up to ∼50 Hz. These findings highlight the importance of spike timing in shaping the quality of a sensation and will contribute to the development of encoding strategies for conveying touch feedback through bionic hands and feet.SIGNIFICANCE STATEMENT A major challenge in the study of neural coding of touch has been to understand how temporal patterns in neuronal responses shape the sensory experience. We address this question by varying the pulse frequency (PF) of electrical pulse trains delivered through implanted nerve interfaces in seven amputees. We concomitantly vary pulse width to separate the effect of changing PF on sensory quality from its effect on perceived magnitude. We find that increases in PF lead to increases in perceived frequency, a qualitative dimension, up to ∼50 Hz, beyond which changes in PF have little impact on quality. We conclude that temporal patterning in the neuronal response can shape quality and discuss the implications for restoring touch via neural interfaces.

Ultraflexible and Stretchable Intrafascicular Peripheral Nerve Recording Device with Axon-Dimension, Cuff-Less Microneedle Electrode Array.

Peripheral nerve mapping tools with higher spatial resolution are needed to advance systems neuroscience, and potentially provide a closed-loop biomarker in neuromodulation applications. Two critical challenges of microscale neural interfaces are 1) how to apply them to small peripheral nerves, and 2) how to minimize chronic reactivity. A flexible microneedle nerve array (MINA) is developed, which is the first high-density penetrating electrode array made with axon-sized silicon microneedles embedded in low-modulus thin silicone. The design, fabrication, acute recording, and chronic reactivity to an implanted MINA, are presented. Distinctive units are identified in the rat peroneal nerve. The authors also demonstrate a long-term, cuff-free, and suture-free fixation manner using rose bengal as a light-activated adhesive for two time-points. The tissue response is investigated at 1-week and 6-week time-points, including two sham groups and two MINA-implanted groups. These conditions are quantified in the left vagus nerve of rats using histomorphometry. Micro computed tomography (micro-CT) is added to visualize and quantify tissue encapsulation around the implant. MINA demonstrates a reduction in encapsulation thickness over previously quantified interfascicular methods. Future challenges include techniques for precise insertion of the microneedle electrodes and demonstrating long-term recording.

Engineering strategies towards overcoming bleeding and glial scar formation around neural probes.

Neural probes are sophisticated electrophysiological tools used for intra-cortical recording and stimulation. These microelectrode arrays, designed to penetrate and interface the brain from within, contribute at the forefront of basic and clinical neuroscience. However, one of the challenges and currently most significant limitations is their 'seamless' long-term integration into the surrounding brain tissue. Following implantation, which is typically accompanied by bleeding, the tissue responds with a scarring process, resulting in a gliotic region closest to the probe. This glial scarring is often associated with neuroinflammation, neurodegeneration, and a leaky blood-brain interface (BBI). The engineering progress on minimizing this reaction in the form of improved materials, microfabrication, and surgical techniques is summarized in this review. As research over the past decade has progressed towards a more detailed understanding of the nature of this biological response, it is time to pose the question: Are penetrating probes completely free from glial scarring at all possible?

Microgaskets for High-Channel-Density Reconnectable Implantable Packaging.

Demands for implantable bioelectronic devices to increase the number of channels for greater functional capacity and resolution, shrink implant size to minimize tissue response and patient burden, and support battery changes and electronics upgrades for long-term operational viability, cannot be met with existing implant-connector technology. In this paper we describe our novel approach to develop a rematable high-channel-density implant-connector technology, with a focus on the design, fabrication, and characterization of its microgasket. The microgaskets made of polydimethylsiloxane elastomer (PDMSe) have achieved much better electrical isolation for neural stimulation (~5 MΩ at 10 kHz) compared with conventional implant connectors (50 kΩ at 10 kHz), despite a 200-fold increase in channel density (conventional: ~0.0644 ch/mm2, microgasket: ~12.8 ch/mm2). The microgaskets also achieved high electrical isolation for neural recording (i.e., ~35 MΩ at 1 kHz) at the same high channel density. When mechanically compressed the microscale vias in the PDMSe microgaskets deform laterally, which could damage or enhance gasket-traversing conductive spring elements in each microscale via depending on their design. We have demonstrated that by lowering the height-to-width aspect ratio of the gasket vias, they can maintain their shape under clamping pressures high enough to achieve high isolation.

Bioinspired micro- and nano-structured neural interfaces.

The development of a functional nervous system requires neurons to interact with and promptly respond to a wealth of biochemical, mechanical and topographical cues found in the neural extracellular matrix (ECM). Among these, ECM topographical cues have been found to strongly influence neuronal function and behavior. Here, we discuss how the blueprint of the architectural organization of the brain ECM has been tremendously useful as a source of inspiration to design biomimetic substrates to enhance neural interfaces and dictate neuronal behavior at the cell-material interface. In particular, we focus on different strategies to recapitulate cell-ECM and cell-cell interactions. In order to mimic cell-ECM interactions, we introduce roughness as a first approach to provide informative topographical biomimetic cues to neurons. We then examine 3D scaffolds and hydrogels, as softer 3D platforms for neural interfaces. Moreover, we will discuss how anisotropic features such as grooves and fibers, recapitulating both ECM fibrils and axonal tracts, may provide recognizable paths and tracks that neuron can follow as they develop and establish functional connections. Finally, we show how isotropic topographical cues, recapitulating shapes, and geometries of filopodia- and mushroom-like dendritic spines, have been instrumental to better reproduce neuron-neuron interactions for applications in bioelectronics and neural repair strategies. The high complexity of the brain architecture makes the quest for the fabrication of create more biologically relevant biomimetic architectures in continuous and fast development. Here, we discuss how recent advancements in two-photon polymerization and remotely reconfigurable dynamic interfaces are paving the way towards to a new class of smart biointerfaces forin vitroapplications spanning from neural tissue engineering as well as neural repair strategies.

Irreversible, Self-Aligned Microfluidic Packaging for Chronic Implant Applications.

Packaging is an often overlooked component in microfluidic devices for biomedical implant applications. Robust and reliable connectors to interface microscale and macroscale features are especially critical for chronic implant applications. Existing microfluidic packaging methods are incompatible with emerging polymeric materials designed to enhance device integration with the surrounding tissue. A microfluidic connector scheme was developed to promote compatibility with novel materials and implant applications. The connectors and an adhesive wax were printed on a scaffold via additive manufacturing processes. The low-temperature packaging process entailed bonding the connector to a polymer nanocomposite-based intracortical microfluidic probe using an adhesive wax. The robustness of the packaging was assessed by measuring the tensile and shear bond strengths of the connector-adhesive wax-polymer film interface. After soak testing for 4 weeks, the bond strength continued to exceed the force required to infuse fluids through the microfluidic channel. Further, the shear bond strength exceeded typical probe insertion forces by at least 10-fold. These results support the use of the connector and thermal bonding method as a viable option for chronic implant applications.

Hybrid Electrical and Optical Neural Interfaces.

Neural interfaces bridge the nervous system and the outside world by recording and stimulating neurons. Combining electrical and optical modalities in a single, hybrid neural interface system could lead to complementary and powerful new ways to explore the brain. It has gained robust and exciting momentum recently in neuroscience and neural engineering research. Here, we review developments in the past several years aiming to achieve such hybrid electrical and optical microsystem platforms. Specifically, we cover three major categories of technological advances: transparent neuroelectrodes, optical neural fibers with electrodes, and neural probes/grids integrating electrodes and microscale light-emitting diodes. We discuss examples of these probes tailored to combine electrophysiological recording with optical imaging or optical neural stimulation of the brain and possible directions of future innovation.

Multimode Optical Fibers for Optical Neural Interfaces.

Although multiphoton microscopy enables optical control and monitoring of neural activity with single cells resolution over a depth of several hundreds of micrometers, the scattering nature of the brain tissue requires implantable optical neural interfaces to access subcortical structures. If micro light-emitting devices (µLEDs) and solid-state waveguides represent important technological advancements for the field, multimodal optical fibers (MMFs) are still the most diffused tool in neuroscience labs to interface with deep regions of the brain. At a first glance, MMFs can be seen as very limited systems. However, new studies and discoveries in optics, photonics, and technological solutions for their application to neuroscience research have enabled applications of MMF where competing technologies fail. In this framework, the chapter starts with a description of optical neural interfaces based on MMF, with specific reference on recent works analyzing the performances of this approach to deliver and collect light from scattering tissue. The discussion then focuses on how peculiar features of MMFs can be exploited to obtain unconventional applications, including brain imaging through a single multimode fiber, multifunctional neural interfaces, and depth-resolved light delivery and functional fluorescence collection.

POEMS (POLYMERIC OPTO-ELECTRO-MECHANICAL SYSTEMS) FOR ADVANCED NEURAL INTERFACES.

There has been a growing interest in optical neural interfaces which is driven by the need for improvements in spatial precision, real-time monitoring, and reduced invasiveness. Here, we present unique microfabrication and packaging techniques to build implantable optoelectronics with high precision and spatial complexity. Material characterization of our hybrid polymers shows minimal in vitro degradation, greater flexibility, and lowest optical loss (4.04-4.4 dB/cm at 670 nm) among other polymers reported in prior studies. We use the developed methods to build Lawrence Livermore National Laboratory's (LLNL's) first ultra-compact, lightweight (0.38 g), scalable and minimally invasive thin-film optoelectronic neural implant that can be used for chronic studies of brain activities. The paper concludes by summarizing the progress to date and discussing future opportunities for flexible optoelectronic interfaces in next generation clinical applications.

Modular Data Acquisition System for Recording Activity and Electrical Stimulation of Brain Tissue Using Dedicated Electronics.

In this paper, we present a modular Data Acquisition (DAQ) system for simultaneous electrical stimulation and recording of brain activity. The DAQ system is designed to work with custom-designed Application Specific Integrated Circuit (ASIC) called Neurostim-3 and a variety of commercially available Multi-Electrode Arrays (MEAs). The system can control simultaneously up to 512 independent bidirectional i.e., input-output channels. We present in-depth insight into both hardware and software architectures and discuss relationships between cooperating parts of that system. The particular focus of this study was the exploration of efficient software design so that it could perform all its tasks in real-time using a standard Personal Computer (PC) without the need for data precomputation even for the most demanding experiment scenarios. Not only do we show bare performance metrics, but we also used this software to characterise signal processing capabilities of Neurostim-3 (e.g., gain linearity, transmission band) so that to obtain information on how well it can handle neural signals in real-world applications. The results indicate that each Neurostim-3 channel exhibits signal gain linearity in a wide range of input signal amplitudes. Moreover, their high-pass cut-off frequency gets close to 0.6Hz making it suitable for recording both Local Field Potential (LFP) and spiking brain activity signals. Additionally, the current stimulation circuitry was checked in terms of the ability to reproduce complex patterns. Finally, we present data acquired using our system from the experiments on a living rat's brain, which proved we obtained physiological data from non-stimulated and stimulated tissue. The presented results lead us to conclude that our hardware and software can work efficiently and effectively in tandem giving valuable insights into how information is being processed by the brain.

Converging Robotic Technologies in Targeted Neural Rehabilitation: A Review of Emerging Solutions and Challenges.

Recent advances in the field of neural rehabilitation, facilitated through technological innovation and improved neurophysiological knowledge of impaired motor control, have opened up new research directions. Such advances increase the relevance of existing interventions, as well as allow novel methodologies and technological synergies. New approaches attempt to partially overcome long-term disability caused by spinal cord injury, using either invasive bridging technologies or noninvasive human-machine interfaces. Muscular dystrophies benefit from electromyography and novel sensors that shed light on underlying neuromotor mechanisms in people with Duchenne. Novel wearable robotics devices are being tailored to specific patient populations, such as traumatic brain injury, stroke, and amputated individuals. In addition, developments in robot-assisted rehabilitation may enhance motor learning and generate movement repetitions by decoding the brain activity of patients during therapy. This is further facilitated by artificial intelligence algorithms coupled with faster electronics. The practical impact of integrating such technologies with neural rehabilitation treatment can be substantial. They can potentially empower nontechnically trained individuals-namely, family members and professional carers-to alter the programming of neural rehabilitation robotic setups, to actively get involved and intervene promptly at the point of care. This narrative review considers existing and emerging neural rehabilitation technologies through the perspective of replacing or restoring functions, enhancing, or improving natural neural output, as well as promoting or recruiting dormant neuroplasticity. Upon conclusion, we discuss the future directions for neural rehabilitation research, diagnosis, and treatment based on the discussed technologies and their major roadblocks. This future may eventually become possible through technological evolution and convergence of mutually beneficial technologies to create hybrid solutions.

Compensation Strategies for Bioelectric Signal Changes in Chronic Selective Nerve Cuff Recordings: A Simulation Study.

Peripheral nerve interfaces (PNIs) allow us to extract motor, sensory, and autonomic information from the nervous system and use it as control signals in neuroprosthetic and neuromodulation applications. Recent efforts have aimed to improve the recording selectivity of PNIs, including by using spatiotemporal patterns from multi-contact nerve cuff electrodes as input to a convolutional neural network (CNN). Before such a methodology can be translated to humans, its performance in chronic implantation scenarios must be evaluated. In this simulation study, approaches were evaluated for maintaining selective recording performance in the presence of two chronic implantation challenges: the growth of encapsulation tissue and rotation of the nerve cuff electrode. Performance over time was examined in three conditions: training the CNN at baseline only, supervised re-training with explicitly labeled data at periodic intervals, and a semi-supervised self-learning approach. This study demonstrated that a selective recording algorithm trained at baseline will likely fail over time due to changes in signal characteristics resulting from the chronic challenges. Results further showed that periodically recalibrating the selective recording algorithm could maintain its performance over time, and that a self-learning approach has the potential to reduce the frequency of recalibration.

Future of Neural Interfaces.

The technological ability to capture electrophysiological activity of populations of cortical neurons through chronic implantable devices has led to significant advancements in the field of brain-computer interfaces. Recent progress in the field has been driven by developments in integrated microelectronics, wireless communications, materials science, and computational neuroscience. Here, we review major device development landmarks in the arena of neural interfaces from FDA-approved clinical systems to prototype head-mounted and fully implantable wireless systems for multi-channel neural recording. Additionally, we provide an outlook toward next-generation, highly miniaturized technologies for minimally invasive, vastly parallel neural interfaces for naturalistic, closed-loop neuroprostheses.