Engineered functional neural interfaces (fNIs) serve as essential abiotic–biotic transducers between an engineered system and the nervous system. They convert external physical stimuli to cellular signals in stimulation mode or read out biological processes in recording mode. Information can be exchanged using electricity, light, magnetic fields, mechanical forces, heat, or chemical signals. fNIs have found applications for studying processes in neural circuits from cell cultures to organs to whole organisms. fNI-facilitated signal transduction schemes, coupled with easily manipulable and observable external physical signals, have attracted considerable attention in recent years. This enticing field is rapidly evolving toward miniaturization and biomimicry to achieve long-term interface stability with great signal transduction efficiency. Not only has a new generation of neuroelectrodes been invented, but the use of advanced fNIs that explore other physical modalities of neuromodulation and recording has begun to increase. This review covers these exciting developments and applications of fNIs that rely on nanoelectrodes, nanotransducers, or bionanotransducers to establish an interface with the nervous system. These nano fNIs are promising in offering a high spatial resolution, high target specificity, and high communication bandwidth by allowing for a high density and count of signal channels with minimum material volume and area to dramatically improve the chronic integration of the fNI to the target neural tissue. Such demanding advances in nano fNIs will greatly facilitate new opportunities not only for studying basic neuroscience but also for diagnosing and treating various neurological diseases.
Background Despite significant advancements of optical imaging techniques for mapping hemodynamics in small animal models, it remains challenging to combine imaging with spatially resolved electrical recording of individual neurons especially for longitudinal studies. This is largely due to the strong invasiveness to the living brain from the penetrating electrodes and their limited compatibility with longitudinal imaging.
Understanding brain functions at the circuit level requires time-resolved simultaneous measurement of a large number of densely distributed neurons, which remains a great challenge for current neural technologies. In particular, penetrating neural electrodes allow for recording from individual neurons at high temporal resolution, but often have larger dimensions than the biological matrix, which induces significant damage to brain tissues and therefore precludes the high implant density that is necessary for mapping large neuronal populations with full coverage. Here, it is demonstrated that nanofabricated ultraflexible electrode arrays with cross-sectional areas as small as sub-10 µm2 can overcome this physical limitation. In a mouse model, it is shown that these electrodes record action potentials with high signal-to-noise ratio; their dense arrays allow spatial oversampling; and their multiprobe implantation allows for interprobe spacing at 60 µm without eliciting chronic neuronal degeneration. These results present the possibility of minimizing tissue displacement by implanted ultraflexible electrodes for scalable, high-density electrophysiological recording that is capable of complete neuronal circuitry mapping over chronic time scales.
Brain function can be best studied by simultaneous measurements and modulation of the multifaceted signaling at the cellular scale. Extensive efforts have been made to develop multifunctional neural probes, typically involving highly specialized fabrication processes. Here, we report a novel multifunctional neural probe platform realized by applying ultra-thin nanoelectronic coating (NEC) on the surfaces of conventional microscale devices such as optical fibers and micropipettes. We fabricated the NECs by planar photolithography techniques using a substrate-less and multi-layer design, which host arrays of individually addressed electrodes with an overall thickness below 1 µm. Guided by an analytic model and taking advantage of the surface tension, we precisely aligned and coated the NEC devices on the surfaces of these conventional micro-probes, and enabled electrical recording capabilities on par with the state-of-the-art neural electrodes. We further demonstrated optogenetic stimulation and controlled drug infusion with simultaneous, spatially resolved neural recording in a rodent model. This study provides a low-cost, versatile approach to construct multifunctional neural probes that can be applied to both fundamental and translational neuroscience.
Fibrosis and hence capsule formation around the glaucoma implants are the main reasons for glaucoma implant failure. To address these issues, we designed a microfluidic meshwork and tested its biocompatibility in a rabbit eye model. The amount of fibrosis elicited by the microfluidic meshwork was compared to the amount elicited by the plate of conventional glaucoma drainage device
Optical manipulation of biological cells and nanoparticles is significantly important in life sciences, early disease diagnosis, and nanomanufacturing. However, low-power and versatile all-optical manipulation has remained elusive. Herein, we have achieved light-directed versatile thermophoretic manipulation of biological cells at an optical power 100–1000 times lower than that of optical tweezers. By harnessing the permittivity gradient in the electric double layer of the charged surface of the cell membrane, we succeed at the low-power trapping of suspended biological cells within a light-controlled temperature gradient field. Furthermore, through dynamic control of optothermal potentials using a digital micromirror device, we have achieved arbitrary spatial arrangements of cells at a resolution of ∼100 nm and precise rotation of both single and assemblies of cells. Our thermophoretic tweezers will find applications in cellular biology, nanomedicine, and tissue engineering.
Implanted brain electrodes construct the only means to electrically interface with individual neurons in vivo, but their recording efficacy and biocompatibility pose limitations on scientific and clinical applications. We showed that nanoelectronic thread (NET) electrodes with subcellular dimensions, ultraflexibility, and cellular surgical footprints form reliable, glial scar–free neural integration. We demonstrated that NET electrodes reliably detected and tracked individual units for months; their impedance, noise level, single-unit recording yield, and the signal amplitude remained stable during long-term implantation. In vivo two-photon imaging and postmortem histological analysis revealed seamless, subcellular integration of NET probes with the local cellular and vasculature networks, featuring fully recovered capillaries with an intact blood-brain barrier and complete absence of chronic neuronal degradation and glial scar.
Rabi splitting that arises from strong plasmon–molecule coupling has attracted tremendous interests. However, it has remained elusive to integrate Rabi splitting into the hybrid plasmon–waveguide modes (HPWMs), which have advantages of both subwavelength light confinement of surface plasmons and long-range propagation of guided modes in dielectric waveguides. Herein, we explore a new type of HPWMs based on hybrid systems of Al nanodisk arrays covered by PMMA thin films that are doped with photochromic molecules and demonstrate the photoswitchable Rabi splitting with a maximum splitting energy of 572 meV in the HPWMs by controlling the photoisomerization of the molecules. Through our experimental measurements combined with finite-difference time-domain (FDTD) simulations, we reveal that the photoswitchable Rabi splitting arises from the switchable coupling between the HPWMs and molecular excitons. By harnessing the photoswitchable Rabi splitting, we develop all-optical light modulators and rewritable waveguides. The demonstration of Rabi splitting in the HPWMs will further advance scientific research and device applications of hybrid plasmon–molecule systems.
Direct electrical recording and stimulation of neural activity using micro-fabricated silicon and metal micro-wire probes have contributed extensively to basic neuroscience and therapeutic applications; however, the dimensional and mechanical mismatch of these probes with the brain tissue limits their stability in chronic implants and decreases the neuron–device contact. Here, we demonstrate the realization of a three-dimensional macroporous nanoelectronic brain probe that combines ultra-flexibility and subcellular feature sizes to overcome these limitations. Built-in strains controlling the local geometry of the macroporous devices are designed to optimize the neuron/probe interface and to promote integration with the brain tissue while introducing minimal mechanical perturbation. The ultra-flexible probes were implanted frozen into rodent brains and used to record multiplexed local field potentials and single-unit action potentials from the somatosensory cortex. Significantly, histology analysis revealed filling-in of neural tissue through the macroporous network and attractive neuron–probe interactions, consistent with long-term biocompatibility of the device.
Seamless and minimally invasive three-dimensional interpenetration of electronics within artificial or natural structures could allow for continuous monitoring and manipulation of their properties. Flexible electronics provide a means for conforming electronics to non-planar surfaces, yet targeted delivery of flexible electronics to internal regions remains difficult. Here, we overcome this challenge by demonstrating the syringe injection (and subsequent unfolding) of sub-micrometre-thick, centimetre-scale macroporous mesh electronics through needles with a diameter as small as 100 μm. Our results show that electronic components can be injected into man-made and biological cavities, as well as dense gels and tissue, with >90% device yield. We demonstrate several applications of syringe-injectable electronics as a general approach for interpenetrating flexible electronics with three-dimensional structures, including (1) monitoring internal mechanical strains in polymer cavities, (2) tight integration and low chronic immunoreactivity with several distinct regions of the brain, and (3) in vivo multiplexed neural recording. Moreover, syringe injection enables the delivery of flexible electronics through a rigid shell, the delivery of large-volume flexible electronics that can fill internal cavities, and co-injection of electronics with other materials into host structures, opening up unique applications for flexible electronics.
Intracellular recording of action potentials is important to understand electrically-excitable cells. Recently, vertical nanoelectrodes have been developed to achieve highly sensitive, minimally invasive and large-scale intracellular recording. It has been demonstrated that the vertical geometry is crucial for the enhanced signal detection. Here we develop nanoelectrodes of a new geometry, namely nanotubes of iridium oxide. When cardiomyocytes are cultured upon those nanotubes, the cell membrane not only wraps around the vertical tubes but also protrudes deep into the hollow centre. We show that this nanotube geometry enhances cell-electrode coupling and results in larger signals than solid nanoelectrodes. The nanotube electrodes also afford much longer intracellular access and are minimally invasive, making it possible to achieve stable recording up to an hour in a single session and more than 8 days of consecutive daily recording. This study suggests that the nanoelectrode performance can be significantly improved by optimizing the electrode geometry.
Nanowire nanoelectronic devices have been exploited as highly sensitive subcellular resolution detectors for recording extracellular and intracellular signals from cells, as well as from natural and engineered/cyborg tissues, and in this capacity open many opportunities for fundamental biological research and biomedical applications. Here we demonstrate the capability to take full advantage of the attractive capabilities of nanowire nanoelectronic devices for long term physiological studies by passivating the nanowire elements with ultrathin metal oxide shells. Studies of Si and Si/aluminum oxide (Al2O3) core/shell nanowires in physiological solutions at 37 °C demonstrate long-term stability extending for at least 100 days in samples coated with 10 nm thick Al2O3 shells. In addition, investigations of nanowires configured as field-effect transistors (FETs) demonstrate that the Si/Al2O3 core/shell nanowire FETs exhibit good device performance for at least 4 months in physiological model solutions at 37 °C. The generality of this approach was also tested with in studies of Ge/Si and InAs nanowires, where Ge/Si/Al2O3 and InAs/Al2O3core/shell materials exhibited stability for at least 100 days in physiological model solutions at 37 °C. In addition, investigations of hafnium oxide-Al2O3 nanolaminated shells indicate the potential to extend nanowire stability well beyond 1 year time scale in vivo. These studies demonstrate that straightforward core/shell nanowire nanoelectronic devices can exhibit the long term stability needed for a range of chronic in vivo studies in animals as well as powerful biomedical implants that could improve monitoring and treatment of disease.
Seamless and minimally invasive integration of 3D electronic circuitry within host materials could enable the development of materials systems that are self-monitoring and allow for communication with external environments. Here, we report a general strategy for preparing ordered 3D interconnected and addressable macroporous nanoelectronic networks from ordered 2D nanowire nanoelectronic precursors, which are fabricated by conventional lithography. The 3D networks have porosities larger than 99%, contain approximately hundreds of addressable nanowire devices, and have feature sizes from the 10-μm scale (for electrical and structural interconnections) to the 10-nm scale (for device elements). The macroporous nanoelectronic networks were merged with organic gels and polymers to form hybrid materials in which the basic physical and chemical properties of the host were not substantially altered, and electrical measurements further showed a >90% yield of active devices in the hybrid materials. The positions of the nanowire devices were located within 3D hybrid materials with ∼14-nm resolution through simultaneous nanowire device photocurrent/confocal microscopy imaging measurements. In addition, we explored functional properties of these hybrid materials, including (i) mapping time-dependent pH changes throughout a nanowire network/agarose gel sample during external solution pH changes, and (ii) characterizing the strain field in a hybrid nanoelectronic elastomer structures subject to uniaxial and bending forces. The seamless incorporation of active nanoelectronic networks within 3D materials reveals a powerful approach to smart materials in which the capabilities of multifunctional nanoelectronics allow for active monitoring and control of host systems.
Light trapping across a wide band of frequencies is important for applications such as solar cells and photodetectors. Here, we demonstrate a new approach to light management by forming whispering-gallery resonant modes inside a spherical nanoshell structure. The geometry of the structure gives rise to a low quality-factor, facilitating the coupling of light into the resonant modes and substantial enhancement of the light path in the active material, thus dramatically improving absorption. Using nanocrystalline silicon (nc-Si) as a model system, we observe broadband absorption enhancement across a large range of incident angles. The absorption of a single layer of 50-nm-thick spherical nanoshells is equivalent to a 1-μm-thick planar nc-Si film. This light-trapping structure could enable the manufacturing of high-throughput ultra-thin film absorbers in a variety of material systems that demand shorter deposition time, less material usage and transferability to flexible substrates.
Vertically aligned nanopillars can serve as excellent electrical, optical and mechanical platforms for biological studies. However, revealing the nature of the interface between the cell and the nanopillar is very challenging. In particular, a matter of debate is whether the cell membrane remains intact around the nanopillar. Here we present a detailed characterization of the cell-nanopillar interface by transmission electron microscopy. We examined cortical neurons growing on nanopillars with diameter 50–500 nm and heights 0.5–2 μm. We found that on nanopillars less than 300 nm in diameter, the cell membrane wraps around the entirety of the nanopillar without the nanopillar penetrating into the interior of the cell. On the other hand, the cell sits on top of arrays of larger, closely spaced nanopillars. We also observed that the membrane-surface gap of both cell bodies and neurites is smaller for nanopillars than for a flat substrate. These results support a tight interaction between the cell membrane and the nanopillars and previous findings of excellent sealing in electrophysiology recordings using nanopillar electrodes.
Action potentials have a central role in the nervous system and in many cellular processes, notably those involving ion channels. The accurate measurement of action potentials requires efficient coupling between the cell membrane and the measuring electrodes. Intracellular recording methods such as patch clamping involve measuring the voltage or current across the cell membrane by accessing the cell interior with an electrode, allowing both the amplitude and shape of the action potentials to be recorded faithfully with high signal-to-noise ratios1. However, the invasive nature of intracellular methods usually limits the recording time to a few hours1, and their complexity makes it difficult to simultaneously record more than a few cells. Extracellular recording methods, such as multielectrode arrays2 and multitransistor arrays3, are non-invasive and allow long-term and multiplexed measurements. However, extracellular recording sacrifices the one-to-one correspondence between the cells and electrodes, and also suffers from significantly reduced signal strength and quality. Extracellular techniques are not, therefore, able to record action potentials with the accuracy needed to explore the properties of ion channels. As a result, the pharmacological screening of ion-channel drugs is usually performed by low-throughput intracellular recording methods4. The use of nanowire transistors5, 6, 7, nanotube-coupled transistors8 and micro gold-spine and related electrodes9, 10, 11, 12 can significantly improve the signal strength of recorded action potentials. Here, we show that vertical nanopillar electrodes can record both the extracellular and intracellular action potentials of cultured cardiomyocytes over a long period of time with excellent signal strength and quality. Moreover, it is possible to repeatedly switch between extracellular and intracellular recording by nanoscale electroporation and resealing processes. Furthermore, vertical nanopillar electrodes can detect subtle changes in action potentials induced by drugs that target ion channels.
We report a microfluidic positioning chamber (MPC) that can rapidly and repeatedly relocate the same imaging area on a microscope stage. The “roof” of the microfluidic chamber was printed with serials of coordinate numbers that act as positioning marks for mammalian cells that grow attached to the “floor” of the microfluidic chamber. MPC cell culture chamber provided a simple solution for tracking the same cell or groups of cells over days or weeks. The positioning marks were used to register time-lapse images of the same imaging area to single-pixel accuracy. Using MPC cell culture chamber, we tracked the migration, division and differentiation of individual PC12 cells for over a week using bright field and fluorescence imaging.
Observing individual molecules in a complex environment by fluorescence microscopy is becoming increasingly important in biological and medical research, for which critical reduction of observation volume is required. Here, we demonstrate the use of vertically aligned silicon dioxide nanopillars to achieve below-the-diffraction-limit observation volume in vitro and inside live cells. With a diameter much smaller than the wavelength of visible light, a transparent silicon dioxide nanopillar embedded in a nontransparent substrate restricts the propagation of light and affords evanescence wave excitation along its vertical surface. This effect creates highly confined illumination volume that selectively excites fluorescence molecules in the vicinity of the nanopillar. We show that this nanopillar illumination can be used for in vitro single-molecule detection at high fluorophore concentrations. In addition, we demonstrate that vertical nanopillars interface tightly with live cells and function as highly localized light sources inside the cell. Furthermore, specific chemical modification of the nanopillar surface makes it possible to locally recruit proteins of interest and simultaneously observe their behavior within the complex, crowded environment of the cell.