Novel electrode technologies for neural recordings.

Neural recording electrode technologies have contributed considerably to neuroscience by enabling the extracellular detection of low-frequency local field potential oscillations and high-frequency action potentials of single units. Nevertheless, several long-standing limitations exist, including low multiplexity, deleterious chronic immune responses and long-term recording instability. Driven by initiatives encouraging the generation of novel neurotechnologies and the maturation of technologies to fabricate high-density electronics, novel electrode technologies are emerging. Here, we provide an overview of recently developed neural recording electrode technologies with high spatial integration, long-term stability and multiple functionalities. We describe how these emergent neurotechnologies can approach the ultimate goal of illuminating chronic brain activity with minimal disruption of the neural environment, thereby providing unprecedented opportunities for neuroscience research in the future.

Author Correction: Novel electrode technologies for neural recordings.

In part b of Figure 2 in this article, the left bounds of the boxes representing the spatiotemporal resolution of 'EEG/MEG' and 'ECoG' were incorrect. Specifically, the limits of highest temporal resolution for EEG/MEG and ECoG were shown as ~200 ms and ~10 ms and are now corrected to ~2 ms and < 1 ms, respectively. In addition, the lower bounds of the boxes representing 'fMRI/PET' and 'EEG/MEG' incorrectly showed the highest spatial resolution limits of these technologies as ~1 mm and have been corrected to <1 mm and <10 mm, respectively. The upper bound of the 'Implantable electrical probes' box also incorrectly showed the spatial span as ~0.1 mm and has been corrected to between 0.1 and 1 mm due to different spans in different dimensions. The figure has been updated in the online version of the article.

Injectable Ventral Spinal Stimulator Evokes Programmable and Biomimetic Hindlimb Motion.

Spinal cord neuromodulation can restore partial to complete loss of motor functions associated with neuromotor disease and trauma. Current technologies have made substantial progress but have limitations as dorsal epidural or intraspinal devices that are either remote to ventral motor neurons or subject to surgical intervention in the spinal tissue. Here, we describe a flexible and stretchable spinal stimulator design with nanoscale thickness that can be implanted by minimally invasive injection through a polymeric catheter to target the ventral spinal space of mice. Ventrolaterally implanted devices exhibited substantially lower stimulation threshold currents and more precise recruitment of motor pools than did comparable dorsal epidural implants. Functionally relevant and novel hindlimb movements were achieved via specific stimulation patterns of the electrodes. This approach holds translational potential for improving controllable limb function following spinal cord injury or neuromotor disease.

Scalable Three-Dimensional Recording Electrodes for Probing Biological Tissues.

Electrophysiological recording technologies can provide critical insight into the function of the nervous system and other biological tissues. Standard silicon-based probes have limitations, including single-sided recording sites and intrinsic instabilities due to the probe stiffness. Here, we demonstrate high-performance neural recording using double-sided three-dimensional (3D) electrodes integrated in an ultraflexible bioinspired open mesh structure, allowing electrodes to sample fully the 3D interconnected tissue of the brain. In vivo electrophysiological recording using 3D electrodes shows statistically significant increases in the number of neurons per electrode, average spike amplitudes, and signal to noise ratios in comparison to standard two-dimensional electrodes, while achieving stable detection of single-neuron activity over months. The capability of these 3D electrodes is further shown for chronic recording from retinal ganglion cells in mice. This approach opens new opportunities for a comprehensive 3D interrogation, stimulation, and understanding of the complex circuitry of the brain and other electrogenic tissues in live animals over extended time periods.

All-Tissue-like Multifunctional Optoelectronic Mesh for Deep-Brain Modulation and Mapping.

The development of a multifunctional device that achieves optogenetic neuromodulation and extracellular neural mapping is crucial for understanding neural circuits and treating brain disorders. Although various devices have been explored for this purpose, it is challenging to develop biocompatible optogenetic devices that can seamlessly interface with the brain. Herein, we present a tissue-like optoelectronic mesh with a compact interface that enables not only high spatial and temporal resolutions of optical stimulation but also the sampling of optically evoked neural activities. An in vitro experiment in hydrogel showed efficient light propagation through a freestanding SU-8 waveguide that was integrated with flexible mesh electronics. Additionally, an in vivo implantation of the tissue-like optoelectronic mesh in the brain of a live transgenic mouse enabled the sampling of optically evoked neural signals. Therefore, this multifunctional device can aid the chronic modulation of neural circuits and behavior studies for developing biological and therapeutic applications.

Nanowired Bioelectric Interfaces.

Biological systems have evolved biochemical, electrical, mechanical, and genetic networks to perform essential functions across various length and time scales. High-aspect-ratio biological nanowires, such as bacterial pili and neurites, mediate many of the interactions and homeostasis in and between these networks. Synthetic materials designed to mimic the structure of biological nanowires could also incorporate similar functional properties, and exploiting this structure-function relationship has already proved fruitful in designing biointerfaces. Semiconductor nanowires are a particularly promising class of synthetic nanowires for biointerfaces, given (1) their unique optical and electronic properties and (2) their high degree of synthetic control and versatility. These characteristics enable fabrication of a variety of electronic and photonic nanowire devices, allowing for the formation of well-defined, functional bioelectric interfaces at the biomolecular level to the whole-organ level. In this Focus Review, we first discuss the history of bioelectric interfaces with semiconductor nanowires. We next highlight several important, endogenous biological nanowires and use these as a framework to categorize semiconductor nanowire-based biointerfaces. Within this framework we then review the fundamentals of bioelectric interfaces with semiconductor nanowires and comment on both material choice and device design to form biointerfaces spanning multiple length scales. We conclude with a discussion of areas with the potential for greatest impact using semiconductor nanowire-enabled biointerfaces in the future.

Bioinspired neuron-like electronics.

As an important application of functional biomaterials, neural probes have contributed substantially to studying the brain. Bioinspired and biomimetic strategies have begun to be applied to the development of neural probes, although these and previous generations of probes have had structural and mechanical dissimilarities from their neuron targets that lead to neuronal loss, neuroinflammatory responses and measurement instabilities. Here, we present a bioinspired design for neural probes-neuron-like electronics (NeuE)-where the key building blocks mimic the subcellular structural features and mechanical properties of neurons. Full three-dimensional mapping of implanted NeuE-brain interfaces highlights the structural indistinguishability and intimate interpenetration of NeuE and neurons. Time-dependent histology and electrophysiology studies further reveal a structurally and functionally stable interface with the neuronal and glial networks shortly following implantation, thus opening opportunities for next-generation brain-machine interfaces. Finally, the NeuE subcellular structural features are shown to facilitate migration of endogenous neural progenitor cells, thus holding promise as an electrically active platform for transplantation-free regenerative medicine.

Highly scalable multichannel mesh electronics for stable chronic brain electrophysiology.

Implantable electrical probes have led to advances in neuroscience, brain-machine interfaces, and treatment of neurological diseases, yet they remain limited in several key aspects. Ideally, an electrical probe should be capable of recording from large numbers of neurons across multiple local circuits and, importantly, allow stable tracking of the evolution of these neurons over the entire course of study. Silicon probes based on microfabrication can yield large-scale, high-density recording but face challenges of chronic gliosis and instability due to mechanical and structural mismatch with the brain. Ultraflexible mesh electronics, on the other hand, have demonstrated negligible chronic immune response and stable long-term brain monitoring at single-neuron level, although, to date, it has been limited to 16 channels. Here, we present a scalable scheme for highly multiplexed mesh electronics probes to bridge the gap between scalability and flexibility, where 32 to 128 channels per probe were implemented while the crucial brain-like structure and mechanics were maintained. Combining this mesh design with multisite injection, we demonstrate stable 128-channel local field potential and single-unit recordings from multiple brain regions in awake restrained mice over 4 mo. In addition, the newly integrated mesh is used to validate stable chronic recordings in freely behaving mice. This scalable scheme for mesh electronics together with demonstrated long-term stability represent important progress toward the realization of ideal implantable electrical probes allowing for mapping and tracking single-neuron level circuit changes associated with learning, aging, and neurodegenerative diseases.

Syringe-injectable mesh electronics integrate seamlessly with minimal chronic immune response in the brain.

Implantation of electrical probes into the brain has been central to both neuroscience research and biomedical applications, although conventional probes induce gliosis in surrounding tissue. We recently reported ultraflexible open mesh electronics implanted into rodent brains by syringe injection that exhibit promising chronic tissue response and recording stability. Here we report time-dependent histology studies of the mesh electronics/brain-tissue interface obtained from sections perpendicular and parallel to probe long axis, as well as studies of conventional flexible thin-film probes. Confocal fluorescence microscopy images of the perpendicular and parallel brain slices containing mesh electronics showed that the distribution of astrocytes, microglia, and neurons became uniform from 2-12 wk, whereas flexible thin-film probes yield a marked accumulation of astrocytes and microglia and decrease of neurons for the same period. Quantitative analyses of 4- and 12-wk data showed that the signals for neurons, axons, astrocytes, and microglia are nearly the same from the mesh electronics surface to the baseline far from the probes, in contrast to flexible polymer probes, which show decreases in neuron and increases in astrocyte and microglia signals. Notably, images of sagittal brain slices containing nearly the entire mesh electronics probe showed that the tissue interface was uniform and neurons and neurofilaments penetrated through the mesh by 3 mo postimplantation. The minimal immune response and seamless interface with brain tissue postimplantation achieved by ultraflexible open mesh electronics probes provide substantial advantages and could enable a wide range of opportunities for in vivo chronic recording and modulation of brain activity in the future.

Gate Tunable Hole Charge Qubit Formed in a Ge/Si Nanowire Double Quantum Dot Coupled to Microwave Photons.

A controllable and coherent light-matter interface is an essential element for a scalable quantum information processor. Strong coupling to an on-chip cavity has been accomplished in various electron quantum dot systems, but rarely explored in the hole systems. Here we demonstrate a hybrid architecture comprising a microwave transmission line resonator controllably coupled to a hole charge qubit formed in a Ge/Si core/shell nanowire (NW), which is a natural one-dimensional hole gas with a strong spin-orbit interaction (SOI) and lack of nuclear spin scattering, potentially enabling fast spin manipulation by electric manners and long coherence times. The charge qubit is established in a double quantum dot defined by local electrical gates. Qubit transition energy can be independently tuned by the electrochemical potential difference and the tunnel coupling between the adjacent dots, opening transverse (σ x) and longitudinal (σ z) degrees of freedom for qubit operation and interaction. As the qubit energy is swept across the photon level, the coupling with resonator is thus switched on and off, as detected by resonator transmission spectroscopy. The observed resonance dynamics is replicated by a complete quantum numerical simulation considering an efficient charge dipole-photon coupling with a strength up to 2π × 55 MHz, yielding an estimation of the spin-resonator coupling rate through SOI to be about 10 MHz. The results inspire the future researches on the coherent hole-photon interaction in Ge/Si nanowires.

Advanced One- and Two-Dimensional Mesh Designs for Injectable Electronics.

The unique structure and mechanical properties of syringe-injectable mesh electronics have enabled seamless tissue integration and stable chronic recording of the activities of the same neurons on a year scale. Here, we report studies of a series of structural and mechanical mesh electronics design variations that allow injection using needles at least 4-fold smaller than those previously reported to minimize the footprint during injection of the electronics in soft matter and tissue. Characterization of new ultraflexible two-dimensional (2D) and one-dimensional (1D) probes has demonstrated reproducible injection of the newly developed mesh electronics designs via needles as small as 100 µm in inner diameter (ID) with reduced injection volumes. In vitro hydrogel and in vivo mouse brain studies have shown that ultraflexible 2D and 1D probes maintain their structural integrity and conformation post-injection after being transferred through the reduced diameter needles. In addition, analysis of the variation of the post-injection mesh cross sections suggests a smaller degree of tissue deformation and relaxation with decreasing needle diameters. The capability to implement rational design for mesh electronic probes that can be delivered via much smaller diameter needles should open up new opportunities for integration of electronics with tissue and soft matter in fundamental and translational studies.

Nanoenabled Direct Contact Interfacing of Syringe-Injectable Mesh Electronics.

Polymer-based electronics with low bending stiffnesses and high flexibility, including recently reported macroporous syringe-injectable mesh electronics, have shown substantial promise for chronic studies of neural circuitry in the brains of live animals. A central challenge for exploiting these highly flexible materials for in vivo studies has centered on the development of efficient input/output (I/O) connections to an external interface with high yield, low bonding resistance, and long-term stability. Here we report a new paradigm applied to the challenging case of injectable mesh electronics that exploits the high flexibility of nanoscale thickness two-sided metal I/O pads that can deform and contact standard interface cables in high yield with long-term electrical stability. First, we describe the design and facile fabrication of two-sided metal I/O pads that allow for contact without regard to probe orientation. Second, systematic studies of the contact resistance as a function of I/O pad design and mechanical properties demonstrate the key role of the I/O pad bending stiffness in achieving low-resistance stable contacts. Additionally, computational studies provide design rules for achieving high-yield multiplexed contact interfacing in the case of angular misalignment such that adjacent channels are not shorted. Third, the in vitro measurement of 32-channel mesh electronics probes bonded to interface cables using the direct contact method shows a reproducibly high yield of electrical connectivity. Finally, in vivo experiments with 32-channel mesh electronics probes implanted in live mice demonstrate the chronic stability of the direct contact interface, enabling consistent tracking of single-unit neural activity over at least 2 months without a loss of channel recording. The direct contact interfacing methodology paves the way for scalable long-term connections of multiplexed mesh electronics neural probes for neural recording and modulation and moreover could be used to facilitate a scalable interconnection of other flexible electronics in biological studies and therapeutic applications.

Stable long-term chronic brain mapping at the single-neuron level.

Stable in vivo mapping and modulation of the same neurons and brain circuits over extended periods is critical to both neuroscience and medicine. Current electrical implants offer single-neuron spatiotemporal resolution but are limited by such factors as relative shear motion and chronic immune responses during long-term recording. To overcome these limitations, we developed a chronic in vivo recording and stimulation platform based on flexible mesh electronics, and we demonstrated stable multiplexed local field potentials and single-unit recordings in mouse brains for at least 8 months without probe repositioning. Properties of acquired signals suggest robust tracking of the same neurons over this period. This recording and stimulation platform allowed us to evoke stable single-neuron responses to chronic electrical stimulation and to carry out longitudinal studies of brain aging in freely behaving mice. Such advantages could open up future studies in mapping and modulating changes associated with learning, aging and neurodegenerative diseases.

Mesh Nanoelectronics: Seamless Integration of Electronics with Tissues.

Nanobioelectronics represents a rapidly developing field with broad-ranging opportunities in fundamental biological sciences, biotechnology, and medicine. Despite this potential, seamless integration of electronics has been difficult due to fundamental mismatches, including size and mechanical properties, between the elements of the electronic and living biological systems. In this Account, we discuss the concept, development, key demonstrations, and future opportunities of mesh nanoelectronics as a general paradigm for seamless integration of electronics within synthetic tissues and live animals. We first describe the design and realization of hybrid synthetic tissues that are innervated in three dimensions (3D) with mesh nanoelectronics where the mesh serves as both as a tissue scaffold and as a platform of addressable electronic devices for monitoring and manipulating tissue behavior. Specific examples of tissue/nanoelectronic mesh hybrids highlighted include 3D neural tissue, cardiac patches, and vascular constructs, where the nanoelectronic devices have been used to carry out real-time 3D recording of electrophysiological and chemical signals in the tissues. This novel platform was also exploited for time-dependent 3D spatiotemporal mapping of cardiac tissue action potentials during cell culture and tissue maturation as well as in response to injection of pharmacological agents. The extension to simultaneous real-time monitoring and active control of tissue behavior is further discussed for multifunctional mesh nanoelectronics incorporating both recording and stimulation devices, providing the unique capability of bidirectional interfaces to cardiac tissue. In the case of live animals, new challenges must be addressed, including minimally invasive implantation, absence of deleterious chronic tissue response, and long-term capability for monitoring and modulating tissue activity. We discuss each of these topics in the context of implantation of mesh nanoelectronics into rodent brains. First, we describe the design of ultraflexible mesh nanoelectronics with size features and mechanical properties similar to brain tissue and a novel syringe-injection methodology that allows the mesh nanoelectronics to be precisely delivered to targeted brain regions in a minimally invasive manner. Next, we discuss time-dependent histology studies showing seamless and stable integration of mesh nanoelectronics within brain tissue on at least one year scales without evidence of chronic immune response or glial scarring characteristic of conventional implants. Third, armed with facile input/output interfaces, we describe multiplexed single-unit recordings that demonstrate stable tracking of the same individual neurons and local neural circuits for at least 8 months, long-term monitoring and stimulation of the same groups of neurons, and following changes in individual neuron activity during brain aging. Moving forward, we foresee substantial opportunities for (1) continued development of mesh nanoelectronics through, for example, broadening nanodevice signal detection modalities and taking advantage of tissue-like properties for selective cell targeting and (2) exploiting the unique capabilities of mesh nanoelectronics for tackling critical scientific and medical challenges such as understanding and potentially ameliorating cell and circuit level changes associated with natural and pathological aging, as well as using mesh nanoelectronics as active tissue scaffolds for regenerative medicine and as neuroprosthetics for monitoring and treating neurological diseases.

Specific detection of biomolecules in physiological solutions using graphene transistor biosensors.

Nanomaterial-based field-effect transistor (FET) sensors are capable of label-free real-time chemical and biological detection with high sensitivity and spatial resolution, although direct measurements in high-ionic-strength physiological solutions remain challenging due to the Debye screening effect. Recently, we demonstrated a general strategy to overcome this challenge by incorporating a biomolecule-permeable polymer layer on the surface of silicon nanowire FET sensors. The permeable polymer layer can increase the effective screening length immediately adjacent to the device surface and thereby enable real-time detection of biomolecules in high-ionic-strength solutions. Here, we describe studies demonstrating both the generality of this concept and application to specific protein detection using graphene FET sensors. Concentration-dependent measurements made with polyethylene glycol (PEG)-modified graphene devices exhibited real-time reversible detection of prostate specific antigen (PSA) from 1 to 1,000 nM in 100 mM phosphate buffer. In addition, comodification of graphene devices with PEG and DNA aptamers yielded specific irreversible binding and detection of PSA in pH 7.4 1x PBS solutions, whereas control experiments with proteins that do not bind to the aptamer showed smaller reversible signals. In addition, the active aptamer receptor of the modified graphene devices could be regenerated to yield multiuse selective PSA sensing under physiological conditions. The current work presents an important concept toward the application of nanomaterial-based FET sensors for biochemical sensing in physiological environments and thus could lead to powerful tools for basic research and healthcare.

Helical Hole State in Multiple Conduction Modes in Ge/Si Core/Shell Nanowire.

Helical states, a prerequisite for the engineering of Majorana zero modes in solid-state systems, have recently been reported in the conduction band of III-V nanowires (NWs) subject to strong Rashba spin-orbit interaction. We report the observation of re-entrant conductance features consistent with the presence of helical hole states in multiple conduction modes of a Ge/Si core/shell NW. The Ge/Si system has several potential advantages over electron systems such as longer spin coherence time due to weaker coupling to nuclear spins and the possibility of isotope-purified materials for nuclear spin-free devices. We derive the Landé g factor of 3.6 from magneto-transport measurements, comparable to theoretical predictions and significantly larger when compared with that in strongly confined quantum dots. The spin-orbit energy is evaluated as ∼2.1 meV, on par with values in III-V NWs, showing good agreement with previous theoretical predictions and weak antilocalization measurements.

Tissue-like Neural Probes for Understanding and Modulating the Brain.

Electrophysiology tools have contributed substantially to understanding brain function, yet the capabilities of conventional electrophysiology probes have remained limited in key ways because of large structural and mechanical mismatches with respect to neural tissue. In this Perspective, we discuss how the general goal of probe design in biochemistry, that the probe or label have a minimal impact on the properties and function of the system being studied, can be realized by minimizing structural, mechanical, and topological differences between neural probes and brain tissue, thus leading to a new paradigm of tissue-like mesh electronics. The unique properties and capabilities of the tissue-like mesh electronics as well as future opportunities are summarized. First, we discuss the design of an ultraflexible and open mesh structure of electronics that is tissue-like and can be delivered in the brain via minimally invasive syringe injection like molecular and macromolecular pharmaceuticals. Second, we describe the unprecedented tissue healing without chronic immune response that leads to seamless three-dimensional integration with a natural distribution of neurons and other key cells through these tissue-like probes. These unique characteristics lead to unmatched stable long-term, multiplexed mapping and modulation of neural circuits at the single-neuron level on a year time scale. Last, we offer insights on several exciting future directions for the tissue-like electronics paradigm that capitalize on their unique properties to explore biochemical interactions and signaling in a "natural" brain environment.

Nano-Bioelectronics.

Nano-bioelectronics represents a rapidly expanding interdisciplinary field that combines nanomaterials with biology and electronics and, in so doing, offers the potential to overcome existing challenges in bioelectronics. In particular, shrinking electronic transducer dimensions to the nanoscale and making their properties appear more biological can yield significant improvements in the sensitivity and biocompatibility and thereby open up opportunities in fundamental biology and healthcare. This review emphasizes recent advances in nano-bioelectronics enabled with semiconductor nanostructures, including silicon nanowires, carbon nanotubes, and graphene. First, the synthesis and electrical properties of these nanomaterials are discussed in the context of bioelectronics. Second, affinity-based nano-bioelectronic sensors for highly sensitive analysis of biomolecules are reviewed. In these studies, semiconductor nanostructures as transistor-based biosensors are discussed from fundamental device behavior through sensing applications and future challenges. Third, the complex interface between nanoelectronics and living biological systems, from single cells to live animals, is reviewed. This discussion focuses on representative advances in electrophysiology enabled using semiconductor nanostructures and their nanoelectronic devices for cellular measurements through emerging work where arrays of nanoelectronic devices are incorporated within three-dimensional cell networks that define synthetic and natural tissues. Last, some challenges and exciting future opportunities are discussed.

Friction between van der Waals Solids during Lattice Directed Sliding.

Nanometer-scale crystals of the two-dimensional oxide molybdenum trioxide (MoO3) were formed atop the transition metal dichalcogenides MoS2 and MoSe2. The MoO3 nanocrystals are partially commensurate with the dichalcogenide substrates, being aligned only along one of the substrate's crystallographic axes. These nanocrystals can be slid only along the aligned direction and maintain their alignment with the substrate during motion. Using an AFM probe to oscillate the nanocrystals, it was found that the lateral force required to move them increased linearly with nanocrystal area. The slope of this curve, the interfacial shear strength, was significantly lower than for macroscale systems. It also depended strongly on the duration and the velocity of sliding of the crystal, suggesting a thermal activation model for the system. Finally, it was found that lower commensuration between the nanocrystal and the substrate increased the interfacial shear, a trend opposite that predicted theoretically.

Syringe-Injectable Electronics with a Plug-and-Play Input/Output Interface.

Syringe-injectable mesh electronics represent a new paradigm for brain science and neural prosthetics by virtue of the stable seamless integration of the electronics with neural tissues, a consequence of the macroporous mesh electronics structure with all size features similar to or less than individual neurons and tissue-like flexibility. These same properties, however, make input/output (I/O) connection to measurement electronics challenging, and work to-date has required methods that could be difficult to implement by the life sciences community. Here we present a new syringe-injectable mesh electronics design with plug-and-play I/O interfacing that is rapid, scalable, and user-friendly to nonexperts. The basic design tapers the ultraflexible mesh electronics to a narrow stem that routes all of the device/electrode interconnects to I/O pads that are inserted into a standard zero insertion force (ZIF) connector. Studies show that the entire plug-and-play mesh electronics can be delivered through capillary needles with precise targeting using microliter-scale injection volumes similar to the standard mesh electronics design. Electrical characterization of mesh electronics containing platinum (Pt) electrodes and silicon (Si) nanowire field-effect transistors (NW-FETs) demonstrates the ability to interface arbitrary devices with a contact resistance of only 3 Ω. Finally, in vivo injection into mice required only minutes for I/O connection and yielded expected local field potential (LFP) recordings from a compact head-stage compatible with chronic studies. Our results substantially lower barriers for use by new investigators and open the door for increasingly sophisticated and multifunctional mesh electronics designs for both basic and translational studies.