Single-Crystal Silicon Nanotubes, Hollow Nanocones, and Branched Nanotube Networks.

We report a general approach for the synthesis of single-crystal silicon nanotubes, involving epitaxial deposition of silicon shells on germanium nanowire templates followed by removal of the germanium template by selective wet etching. By exploiting advances in the synthesis of germanium nanowires, we were able to rationally tune the nanotube internal diameters (5-80 nm), wall thicknesses (3-12 nm), and taper angles (0-9°) and additionally demonstrated branched silicon nanotube networks. Field effect transistors fabricated from p-type nanotubes exhibited a strong gate effect, and fluid transport experiments demonstrated that small molecules could be electrophoretically driven through the nanotubes. These results demonstrate the suitability of silicon nanotubes for the design of nanoelectrofluidic devices.

Biochemically functionalized probes for cell-type-specific targeting and recording in the brain.

Selective targeting and modulation of distinct cell types and neuron subtypes is central to understanding complex neural circuitry and could enable electronic treatments that target specific circuits while minimizing off-target effects. However, current brain-implantable electronics have not yet achieved cell-type specificity. We address this challenge by functionalizing flexible mesh electronic probes, which elicit minimal immune response, with antibodies or peptides to target specific cell markers. Histology studies reveal selective association of targeted neurons, astrocytes, and microglia with functionalized probe surfaces without accumulating off-target cells. In vivo chronic electrophysiology further yields recordings consistent with selective targeting of these cell types. Last, probes functionalized to target dopamine receptor 2 expressing neurons show the potential for neuron-subtype-specific targeting and electrophysiology.

Biochemically-functionalized probes for cell type-specific targeting and recording in the brain.

Selective targeting and modulation of distinct cell types and neuron subtypes is central to understanding complex neural circuitry, and could enable electronic treatments that target specific circuits while minimizing off-target effects. However, current brain-implantable electronics have not yet achieved cell-type specificity. We address this challenge by functionalizing flexible mesh electronic probes, which elicit minimal immune response, with antibodies or peptides to target specific cell markers. Histology studies reveal selective association of targeted neurons, astrocytes and microglia with functionalized probe surfaces without accumulating off-target cells. In vivo chronic electrophysiology further yields recordings consistent with selective targeting of these cell types. Last, probes functionalized to target dopamine 2 receptor expressing neurons show the potential for neuron subtype specific targeting and electrophysiology.

Laminin-coated electronic scaffolds with vascular topography for tracking and promoting the migration of brain cells after injury.

In the adult brain, neural stem cells are largely restricted into spatially discrete neurogenic niches, and hence areas of neuron loss during neurodegenerative disease or following a stroke or traumatic brain injury do not typically repopulate spontaneously. Moreover, understanding neural activity accompanying the neural repair process is hindered by a lack of minimally invasive devices for the chronic measurement of the electrophysiological dynamics in damaged brain tissue. Here we show that 32 individually addressable platinum microelectrodes integrated into laminin-coated branched polymer scaffolds stereotaxically injected to span a hydrogel-filled cortical lesion and deeper regions in the brains of mice promote neural regeneration while allowing for the tracking of migrating host brain cells into the lesion. Chronic measurements of single-unit activity and neural-circuit analyses revealed the establishment of spiking activity in new neurons in the lesion and their functional connections with neurons deeper in the brain. Electronic implants mimicking the topographical and surface properties of brain vasculature may aid the stimulation and tracking of neural-circuit restoration following injury.

Ultraflexible endovascular probes for brain recording through micrometer-scale vasculature.

Implantable neuroelectronic interfaces have enabled advances in both fundamental research and treatment of neurological diseases but traditional intracranial depth electrodes require invasive surgery to place and can disrupt neural networks during implantation. We developed an ultrasmall and flexible endovascular neural probe that can be implanted into sub-100-micrometer-scale blood vessels in the brains of rodents without damaging the brain or vasculature. In vivo electrophysiology recording of local field potentials and single-unit spikes have been selectively achieved in the cortex and olfactory bulb. Histology analysis of the tissue interface showed minimal immune response and long-term stability. This platform technology can be readily extended as both research tools and medical devices for the detection and intervention of neurological diseases.

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.

Stitching Flexible Electronics into the Brain.

Understanding complex neuronal networks requires monitoring long-term neuronal activity in various regions of the brain. Significant progress has been made in multisite implantations of well-designed probes, such as multisite implantation of Si-based and polymer-based probes. However, these multiprobe strategies are limited by the sizes and weights of interfaces to the multiple probes and the inability to track the activity of the same neurons and changes in neuronal activity over longer time periods. Here, a long single flexible probe that can be implanted by stitching into multiple regions of the mouse brain and subsequently transmit chronically stable neuronal signals from the multiple sites via a single low-mass interface is reported. The probe at four different sites is implemented using a glass capillary needle or two sites using an ultrathin metal needle. In vitro tests in brain-mimicking hydrogel show that multisite probe implantations achieve a high connection yield of >86%. In vivo histological images at each site of probes, implanted by stitching using either glass capillary or ultrathin metal insertion needles exhibit seamless tissue-probe interfaces with negligible chronic immune response. In addition, electrophysiology studies demonstrate the ability to track single neuron activities at every injection site with chronic stability over at least one month. Notably, the measured spike amplitudes and signal-to-noise ratios at different implantation sites show no statistically significant differences. Multisite stitching implantation of flexible electronics in the brain opens up new opportunities for both fundamental neuroscience research and electrotherapeutic applications.

Ultra-flexible endovascular probes for brain recording through micron-scale vasculature.

Implantable neuroelectronic interfaces have enabled significant advances in both fundamental research and treatment of neurological diseases, yet traditional intracranial depth electrodes require invasive surgery to place and can disrupt the neural networks during implantation. To address these limitations, we have developed an ultra-small and flexible endovascular neural probe that can be implanted into small 100-micron scale blood vessels in the brains of rodents without damaging the brain or vasculature. The structure and mechanical properties of the flexible probes were designed to meet the key constraints for implantation into tortuous blood vessels inaccessible with existing techniques. In vivo electrophysiology recording of local field potentials and single-unit spikes has been selectively achieved in the cortex and the olfactory bulb. Histology analysis of the tissue interface showed minimal immune response and long-term stability. This platform technology can be readily extended as both research tools and medical devices for the detection and intervention of neurological diseases.

Tissue libraries enable rapid determination of conditions that preserve antibody labeling in cleared mouse and human tissue.

Difficulty achieving complete, specific, and homogenous staining is a major bottleneck preventing the widespread use of tissue clearing techniques to image large volumes of human tissue. In this manuscript, we describe a procedure to rapidly design immunostaining protocols for antibody labeling of cleared brain tissue. We prepared libraries of 0.5-1.0 mm thick tissue sections that are fixed, pre-treated, and cleared via similar, but different procedures to optimize staining conditions for a panel of antibodies. Results from a library of mouse tissue correlate well with results from a similarly prepared library of human brain tissue, suggesting mouse tissue is an adequate substitute for protocol optimization. These data show that procedural differences do not influence every antibody-antigen pair in the same way, and minor changes can have deleterious effects, therefore, optimization should be conducted for each target. The approach outlined here will help guide researchers to successfully label a variety of targets, thus removing a major hurdle to accessing the rich 3D information available in large, cleared human tissue volumes.

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.

Nanowire-Enabled Bioelectronics.

Bioelectronics explores the use of electronic devices for applications in signal transduction at their interfaces with biological systems. The miniaturization of the bioelectronic systems has enabled seamless integration at these interfaces and is providing new scientific and technological opportunities. In particular, nanowire-based devices can yield smaller sized and unique geometry detectors that are difficult to access with standard techniques, and thereby can provide advantages in sensitivity with reduced invasiveness. In this review, we focus on nanowire-enabled bioelectronics. First, we provide an overview of synthetic studies for designed growth of semiconductor nanowires of which structure and composition are controlled to enable key elements for bioelectronic devices. Second, we review nanowire field-effect transistor sensors for highly sensitive detection of biomolecules, their applications in diagnosis and drug discovery, and methods for sensitivity enhancement. We then turn to recent progress in nanowire-enabled studies of electrogenic cells, including cardiomyocytes and neurons. Representative advances in electrical recording using nanowire electronic devices for single cell measurements, cell network mapping, and three-dimensional recordings of synthetic and natural tissues, and in vivo brain mapping are highlighted. Finally, we overview the key challenges and opportunities of nanowires for fundamental research and translational applications.

Highly Transparent Contacts to the 1D Hole Gas in Ultrascaled Ge/Si Core/Shell Nanowires.

Semiconductor-superconductor hybrid systems have outstanding potential for emerging high-performance nanoelectronics and quantum devices. However, critical to their successful application is the fabrication of high-quality and reproducible semiconductor-superconductor interfaces. Here, we realize and measure axial Al-Ge-Al nanowire heterostructures with atomically precise interfaces, enwrapped by an ultrathin epitaxial Si layer further denoted as Al-Ge/Si-Al nanowire heterostructures. The heterostructures were synthesized by a thermally induced exchange reaction of single-crystalline Ge/Si core/shell nanowires and lithographically defined Al contact pads. Applying this heterostructure formation scheme enables self-aligned quasi one-dimensional crystalline Al leads contacting ultrascaled Ge/Si segments with contact transparencies greater than 96%. Integration into back-gated field-effect devices and continuous scaling beyond lithographic limitations allows us to exploit the full potential of the highly transparent contacts to the 1D hole gas at the Ge-Si interface. This leads to the observation of ballistic transport as well as quantum confinement effects up to temperatures of 150 K. Low-temperature measurements reveal proximity-induced superconductivity in the Ge/Si core/shell nanowires. The realization of a Josephson field-effect transistor allows us to study the subgap structure caused by multiple Andreev reflections. Most importantly, the absence of a quantum dot regime indicates a hard superconducting gap originating from the highly transparent contacts to the 1D hole gas, which is potentially interesting for the study of Majorana zero modes. Moreover, underlining the importance of the proposed thermally induced Al-Ge/Si-Al heterostructure formation technique, our system could contribute to the development of key components of quantum computing such as gatemon or transmon qubits.

Single-Cell Profiles of Retinal Ganglion Cells Differing in Resilience to Injury Reveal Neuroprotective Genes.

Neuronal types in the central nervous system differ dramatically in their resilience to injury or other insults. Here we studied the selective resilience of mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC), which severs their axons and leads to death of ∼80% of RGCs within 2 weeks. To identify expression programs associated with differential resilience, we first used single-cell RNA-seq (scRNA-seq) to generate a comprehensive molecular atlas of 46 RGC types in adult retina. We then tracked their survival after ONC; characterized transcriptomic, physiological, and morphological changes that preceded degeneration; and identified genes selectively expressed by each type. Finally, using loss- and gain-of-function assays in vivo, we showed that manipulating some of these genes improved neuronal survival and axon regeneration following ONC. This study provides a systematic framework for parsing type-specific responses to injury and demonstrates that differential gene expression can be used to reveal molecular targets for intervention.

Author Correction: Precision electronic medicine in the brain.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Precision electronic medicine in the brain.

Periodically throughout history developments from adjacent fields of science and technology reach a tipping point where together they produce unparalleled advances, such as the Allen Brain Atlas and the Human Genome Project. Today, research focused at the interface between the nervous system and electronics is not only leading to advances in fundamental neuroscience, but also unlocking the potential of implants capable of cellular-level therapeutic targeting. Ultimately, these personalized electronic therapies will provide new treatment modalities for neurodegenerative and neuropsychiatric illness; powerful control of prosthetics for restorative function in degenerative diseases, trauma and amputation; and even augmentation of human cognition. Overall, we believe that emerging advances in tissue-like electronics will enable minimally invasive devices capable of establishing a stable long-term cellular neural interface and providing long-term treatment for chronic neurological conditions.

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.

Scalable ultrasmall three-dimensional nanowire transistor probes for intracellular recording.

New tools for intracellular electrophysiology that push the limits of spatiotemporal resolution while reducing invasiveness could provide a deeper understanding of electrogenic cells and their networks in tissues, and push progress towards human-machine interfaces. Although significant advances have been made in developing nanodevices for intracellular probes, current approaches exhibit a trade-off between device scalability and recording amplitude. We address this challenge by combining deterministic shape-controlled nanowire transfer with spatially defined semiconductor-to-metal transformation to realize scalable nanowire field-effect transistor probe arrays with controllable tip geometry and sensor size, which enable recording of up to 100 mV intracellular action potentials from primary neurons. Systematic studies on neurons and cardiomyocytes show that controlling device curvature and sensor size is critical for achieving high-amplitude intracellular recordings. In addition, this device design allows for multiplexed recording from single cells and cell networks and could enable future investigations of dynamics in the brain and other tissues.

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.

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.