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Recent studies have demonstrated that the mechanisms through which biopolymers like RNA interconvert between multiple folded structures are critical for their cellular functions. A major obstacle to elucidating these mechanisms is the lack of experimental approaches that can resolve these interconversions between functionally relevant biomolecular structures. Here, we dissect the complete set of structural rearrangements executed by an ultra-stable RNA, the UUCG stem-loop, at the single-molecule level using a nano-electronic device with microsecond time resolution. We show that the stem-loop samples at least four conformations along two folding pathways leading to two distinct folded structures, only one of which has been previously observed. By modulating its flexibility, the stem-loop can adaptively select between these pathways, enabling it to both fold rapidly and resist unfolding. This paradigm of stabilization through compensatory changes in flexibility broadens our understanding of stable RNA structures and is expected to serve as a general strategy employed by all biopolymers., Competing Interests: Competing Interests D.G.L. and K.L.S. have a financial interest in Quicksilver Biosciences, Inc., which is commercializing smFET technology for molecular diagnostic applications. The other authors declare no competing financial interest.

Minimally invasive, high-bandwidth brain-computer-interface (BCI) devices can revolutionize human applications. With orders-of-magnitude improvements in volumetric efficiency over other BCI technologies, we developed a 50-μm-thick, mechanically flexible micro-electrocorticography (μECoG) BCI, integrating 256×256 electrodes, signal processing, data telemetry, and wireless powering on a single complementary metal-oxide-semiconductor (CMOS) substrate containing 65,536 recording and 16,384 stimulation channels, from which we can simultaneously record up to 1024 channels at a given time. Fully implanted below the dura, our chip is wirelessly powered, communicating bi-directionally with an external relay station outside the body. We demonstrated chronic, reliable recordings for up to two weeks in pigs and up to two months in behaving non-human primates from somatosensory, motor, and visual cortices, decoding brain signals at high spatiotemporal resolution.

Small molecules such as neurotransmitters are critical for biochemical functions in living systems. While conventional ultraviolet-visible spectroscopy and mass spectrometry lack portability and are unsuitable for time-resolved measurements in situ, techniques such as amperometry and traditional field-effect detection require a large ensemble of molecules to reach detectable signal levels. Here we demonstrate the potential of carbon-nanotube-based single-molecule field-effect transistors (smFETs), which can detect the charge on a single molecule, as a new platform for recognizing and assaying small molecules. smFETs are formed by the covalent attachment of a probe molecule, in our case a DNA aptamer, to a carbon nanotube. Conformation changes on binding are manifest as discrete changes in the nanotube electrical conductance. By monitoring the kinetics of conformational changes in a binding aptamer, we show that smFETs can detect and quantify serotonin at the single-molecule level, providing unique insights into the dynamics of the aptamer-ligand system. In particular, we show the involvement of G-quadruplex formation and the disruption of the native hairpin structure in the conformational changes of the serotonin-aptamer complex. The smFET is a label-free approach to analysing molecular interactions at the single-molecule level with high temporal resolution, providing additional insights into complex biological processes., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Direct deposition of organic light-emitting diodes (OLEDs) on silicon-based complementary metal-oxide-semiconductor (CMOS) chips has enabled self-emissive microdisplays with high resolution and fill-factor. Emerging applications of OLEDs in augmented and virtual reality (AR/VR) displays and in biomedical applications, e.g., as brain implants for cell-specific light delivery in optogenetics, require light intensities orders of magnitude above those found in traditional displays. Further requirements often include a microscopic device footprint, a specific shape and ultrastable passivation, e.g., to ensure biocompatibility and minimal invasiveness of OLED-based implants. In this work, up to 1024 ultrabright, microscopic OLEDs are deposited directly on needle-shaped CMOS chips. Transmission electron microscopy and energy-dispersive X-ray spectroscopy are performed on the foundry-provided aluminum contact pads of the CMOS chips to guide a systematic optimization of the contacts. Plasma treatment and implementation of silver interlayers lead to ohmic contact conditions and thus facilitate direct vacuum deposition of orange- and blue-emitting OLED stacks leading to micrometer-sized pixels on the chips. The electronics in each needle allow each pixel to switch individually. The OLED pixels generate a mean optical power density of 0.25 mW mm -2 , corresponding to >40 000 cd m -2 , well above the requirement for daylight AR applications and optogenetic single-unit activation in the brain., (© 2023 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

The ability to amplify, translate, and process small ionic potential fluctuations of neural processes directly at the recording site is essential to improve the performance of neural implants. Organic front-end analog electronics are ideal for this application, allowing for minimally invasive amplifiers owing to their tissue-like mechanical properties. Here, we demonstrate fully organic complementary circuits by pairing depletion- and enhancement-mode p- and n-type organic electrochemical transistors (OECTs). With precise geometry tuning and a vertical device architecture, we achieve overlapping output characteristics and integrate them into amplifiers with single neuronal dimensions (20 micrometers). Amplifiers with combined p- and n-OECTs result in voltage-to-voltage amplification with a gain of >30 decibels. We also leverage depletion and enhancement-mode p-OECTs with matching characteristics to demonstrate a differential recording capability with high common mode rejection rate (>60 decibels). Integrating OECT-based front-end amplifiers into a flexible shank form factor enables single-neuron recording in the mouse cortex with on-site filtering and amplification.

Due to their effective ionic-to-electronic signal conversion and mechanical flexibility, organic neural implants hold considerable promise for biocompatible neural interfaces. Current approaches are, however, primarily limited to passive electrodes due to a lack of circuit components to realize complex active circuits at the front-end. Here, we introduce a p-n organic electrochemical diode using complementary p- and n-type conducting polymer films embedded in a 15-μm -diameter vertical stack. Leveraging the efficient motion of encapsulated cations inside this polymer stack and the opposite doping mechanisms of the constituent polymers, we demonstrate high current rectification ratios ([Formula: see text]) and fast switching speeds (230 μs). We integrate p-n organic electrochemical diodes with organic electrochemical transistors in the front-end pixel of a recording array. This configuration facilitates the access of organic electrochemical transistor output currents within a large network operating in the same electrolyte, while minimizing crosstalk from neighboring elements due to minimized reverse-biased leakage. Furthermore, we use these devices to fabricate time-division-multiplexed amplifier arrays. Lastly, we show that, when fabricated in a shank format, this technology enables the multiplexing of amplified local field potentials directly in the active recording pixel (26-μm diameter) in a minimally invasive form factor with shank cross-sectional dimensions of only 50×8 [Formula: see text]., (© 2024. The Author(s).)

This paper presents a fully wireless microelectrode array (MEA) system-on-chip (SoC) with 65,536 electrodes for non-penetrative cortical recording and stimulation, featuring a total sensing area of 6.8mm×7.4mm with a 26.5μm×29μm electrode pitch. Sensing, data telemetry, and powering are monolithically integrated on a single chip, which is made mechanically flexible to conform to the surface of the brain by substrate removal to a total thickness of 25μm allowing it to be contained entirely in the subdural space under the skull.

Coronavirus disease (COVID-19) is a contagious respiratory disease caused by the SARS-CoV-2 virus. The clinical phenotypes are variable, ranging from spontaneous recovery to serious illness and death. On March 2020, a global COVID-19 pandemic was declared by the World Health Organization (WHO). As of February 2023, almost 670 million cases and 6,8 million deaths have been confirmed worldwide. Coronaviruses, including SARS-CoV-2, contain a single-stranded RNA genome enclosed in a viral capsid consisting of four structural proteins: the nucleocapsid (N) protein, in the ribonucleoprotein core, the spike (S) protein, the envelope (E) protein, and the membrane (M) protein, embedded in the surface envelope. In particular, the E protein is a poorly characterized viroporin with high identity amongst all the β-coronaviruses (SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43) and a low mutation rate. Here, we focused our attention on the study of SARS-CoV-2 E and M proteins, and we found a general perturbation of the host cell calcium (Ca 2+ ) homeostasis and a selective rearrangement of the interorganelle contact sites. In vitro and in vivo biochemical analyses revealed that the binding of specific nanobodies to soluble regions of SARS-CoV-2 E protein reversed the observed phenotypes, suggesting that the E protein might be an important therapeutic candidate not only for vaccine development, but also for the clinical management of COVID designing drug regimens that, so far, are very limited., (© 2023. The Author(s).)

Scanning ion conductance microscopy (SICM) is a topographic imaging technique capable of probing biological samples in electrolyte conditions. SICM enhancements have enabled surface charge detection based on voltage-dependent signals. Here, we show how the hopping mode SICM method (HP-SICM) can be used for rapid and minimally invasive surface charge mapping. We validate our method using Pseudomonas aeruginosa PA14 (PA) cells and observe a surface charge density of σ PA = -2.0 ± 0.45 mC/m 2 that is homogeneous within the ∼80 nm lateral scan resolution. This biological surface charge is detected from at least 1.7 μm above the membrane (395× the Debye length), and the long-range charge detection is attributed to electroosmotic amplification. We show that imaging with a nanobubble-plugged probe reduces perturbation of the underlying sample. We extend the technique to PA biofilms and observe a charge density exceeding -20 mC/m 2 . We use a solid-state calibration to quantify surface charge density and show that HP-SICM cannot be quantitatively described by a steady-state finite element model. This work contributes to the body of scanning probe methods that can uniquely contribute to microbiology and cellular biology.

Optical neurotechnologies use light to interface with neurons and can monitor and manipulate neural activity with high spatial-temporal precision over large cortical extents. While there has been significant progress in miniaturizing microscope for head-mounted configurations, these existing devices are still very bulky and could never be fully implanted. Any viable translation of these technologies to human use will require a much more noninvasive, fully implantable form factor. Here, we leverage advances in microelectronics and heterogeneous optoelectronic packaging to develop a transformative, ultrathin, miniaturized device for bidirectional optical stimulation and recording: the subdural CMOS Optical Probe (SCOPe). By being thin enough to lie entirely within the subdural space of the primate brain, SCOPe defines a path for the eventual human translation of a new generation of brain-machine interfaces based on light.

We have developed and used single-molecule field-effect transistors (smFETs) to characterize the conformational free-energy landscape of RNA stem-loops. Stem-loops are one of the most common RNA structural motifs and serve as building blocks for the formation of complex RNA structures. Given their prevalence and integral role in RNA folding, the kinetics of stem-loop (un)folding has been extensively characterized using both experimental and computational approaches. Interestingly, these studies have reported vastly disparate timescales of (un)folding, which has been interpreted as evidence that (un)folding of even simple stem-loops occurs on a highly rugged conformational energy landscape. Because smFETs do not rely on fluorophore reporters of conformation or mechanical (un)folding forces, they provide a unique approach that has allowed us to directly monitor tens of thousands of (un)folding events of individual stem-loops at a 200 μs time resolution. Our results show that under our experimental conditions, stem-loops (un)fold over a 1-200 ms timescale during which they transition between ensembles of unfolded and folded conformations, the latter of which is composed of at least two sub-populations. The 1-200 ms timescale of (un)folding we observe here indicates that smFETs report on complete (un)folding trajectories in which unfolded conformations of the RNA spend long periods of time wandering the free-energy landscape before sampling one of several misfolded conformations or the natively folded conformation. Our findings highlight the extremely rugged landscape on which even the simplest RNA structural elements fold and demonstrate that smFETs are a unique and powerful approach for characterizing the conformational free-energy of RNA.

Most neuromodulation approaches rely on extracellular electrical stimulation with penetrating electrodes at the cost of cortical damage. Surface electrodes, in contrast, are much less invasive but are challenged by the lack of proximity to axonal processes, leading to poor resolution. Here, we demonstrate that high-density (40-μm pitch), high-capacitance (>1 nF), single neuronal resolution PEDOT:PSS electrodes can be programmed to shape the charge injection front selectively at depths approaching 300 micrometers with a lateral resolution better than 100 micrometers. These electrodes, patterned on thin-film parylene substrate, can be subdurally implanted and adhere to the pial surface in chronic settings. By leveraging surface arrays that are optically transparent with PEDOT:PSS local interconnects and integrated with depth electrodes, we are able to combine surface stimulation and recording with calcium imaging and depth recording to demonstrate these spatial limits of bidirectional communication with pyramidal neurons in mouse visual cortex both laterally and at depth from the surface.

Ultrasound imaging provides the means for non-invasive real-time diagnostics of the internal structure of soft tissue in living organisms. However, the majority of commercially available ultrasonic transducers have rigid interfaces which cannot conform to highly-curved surfaces. These geometric limitations can introduce a signal-quenching air gap for certain topographies, rendering accurate imaging difficult or impractical. Here, we demonstrate a 256-element flexible two-dimensional (2D) ultrasound piezoelectric transducer array with geometric phase correction. We show surface-conformable real-time B-mode imaging, down to an extreme radius of curvature of 1.5 cm, while maintaining desirable performance metrics such as high signal-to-noise ratio (SNR) and minimal elemental cross-talk at all stages of bending. We benchmark the array capabilities by resolving reflectors buried at known locations in a medical-grade tissue phantom, and demonstrate how phase correction can improve image reconstruction on curved surfaces. With the current array design, we achieve an axial resolution of ≈ 2 mm at clinically-relevant depths in tissue, while operating the array at 1.4 MHz with a bandwidth of ≈ 41%. We use our prototype to image the surface of the human humerus at different positions along the arm, demonstrating proof-of-concept applicability for real-time diagnostics using phase-corrected flexible ultrasound probes., (© 2022. The Author(s).)

Modern clinical practice benefits significantly from imaging technologies and much effort is directed toward making this imaging more informative through the addition of contrast agents or reporters. Here, we report the design of a battery-less integrated circuit mote acting as an electronic reporter during medical ultrasound imaging. When implanted within the field-of-view of a brightness-mode (B-mode) ultrasound imager, this mote transmits information from its location through backscattered acoustic energy which is captured within the ultrasound image itself. We prototype and characterize the operation of such motes in vitro and in vivo. Performing with a static power consumption of less than 57 pW, the motes operate at duty cycles for receiving acoustic energy as low as 50 ppm. Motes within the same field-of-view during imaging have demonstrated signal-to-noise ratios of more than 19.1 dB at depths of up to 40 mm in lossy phantom. Physiological information acquired through such motes, which is beyond what is measurable with endogenous ultrasound backscatter and which is biogeographically located within an image, has the potential to provide an augmented ultrasonography., (© 2022. The Author(s).)

Inverting a semiconducting channel is the basis of all field-effect transistors. In silicon-based metal-oxide-semiconductor field-effect transistors (MOSFETs), a gate dielectric mediates this inversion. Access to inversion layers may be granted by interfacing ultrathin low-dimensional semiconductors in heterojunctions to advance device downscaling. Here we demonstrate that monolayer molybdenum disulfide (MoS 2 ) can directly invert a single-walled semiconducting carbon nanotube (SWCNT) transistor channel without the need for a gate dielectric. We fabricate and study this atomically thin one-dimensional/two-dimensional (1D/2D) van der Waals heterojunction and employ it as the gate of a 1D heterojunction field-effect transistor (1D-HFET) channel. Gate control is based on modulating the conductance through the channel by forming a lateral p-n junction within the CNT itself. In addition, we observe a region of operation exhibiting a negative static resistance after significant gate tunneling current passes through the junction. Technology computer-aided design (TCAD) simulations confirm the role of minority carrier drift-diffusion in enabling this behavior. The resulting van der Waals transistor architecture thus has the dual characteristics of both field-effect and tunneling transistors, and it advances the downscaling of heterostructures beyond the limits of dangling bonds and epitaxial constraints faced by III-V semiconductors.

Implantable image sensors have the potential to revolutionize neuroscience. Due to their small form factor requirements; however, conventional filters and optics cannot be implemented. These limitations obstruct high-resolution imaging of large neural densities. Recent advances in angle-sensitive image sensors and single-photon avalanche diodes have provided a path toward ultrathin lens-less fluorescence imaging, enabling plenoptic sensing by extending sensing capabilities to include photon arrival time and incident angle, thereby providing the opportunity for separability of fluorescence point sources within the context of light-field microscopy (LFM). However, the addition of spectral sensitivity to angle-sensitive LFM reduces imager resolution because each wavelength requires a separate pixel subset. Here, we present a 1024-pixel, 50  µm thick implantable shank-based neural imager with color-filter-grating-based angle-sensitive pixels. This angular-spectral sensitive front end combines a metal-insulator-metal (MIM) Fabry-Perot color filter and diffractive optics to produce the measurement of orthogonal light-field information from two distinct colors within a single photodetector. The result is the ability to add independent color sensing to LFM while doubling the effective pixel density. The implantable imager combines angular-spectral and temporal information to demix and localize multispectral fluorescent targets. In this initial prototype, this is demonstrated with 45 μm diameter fluorescently labeled beads in scattering medium. Fluorescent lifetime imaging is exploited to further aid source separation, in addition to detecting pH through lifetime changes in fluorescent dyes. While these initial fluorescent targets are considerably brighter than fluorescently labeled neurons, further improvements will allow the application of these techniques to in-vivo multifluorescent structural and functional neural imaging., (© 2022. The Author(s).)

Here, we report light emission from single atoms bridging a graphene nanogap that emit bright visible light based on fluorescence of ionized atoms. Oxygen atoms in the gap shows a peak emission wavelength of 569 nm with a full width at half maximum (FWHM) of 208 nm. The energy states produced by these ionized oxygen atoms bridging carbon atoms in the gap also produce a large negative differential resistance (NDR) in the transport across the gap with the highest peak-to-valley current ratio (PVR = 45) and highest peak current density (~90 kA/cm 2 ) ever reported in a solid-state tunneling device. While tunneling transport has been previously observed in graphene nanogaps, the bridging of ionized oxygen observed here shows a low excess current, leading to the observed PVR. On the basis of the highly reproducible light emission and NDR from these structures, we demonstrate a 65,536-pixel light-emitting nanogap array.

Emerging non-imaging ultrasound applications, such as ultrasonic wireless power delivery to implantable devices and ultrasound neuromodulation, require wearable form factors, millisecond-range pulse durations and focal spot diameters approaching 100 μm with electronic control of its three-dimensional location. None of these are compatible with typical handheld linear array ultrasound imaging probes. In this work, we present a 4 mm × 5 mm 2D ultrasound phased array transmitter with integrated piezoelectric ultrasound transducers on complementary metal-oxide-semiconductor (CMOS) integrated circuits, featuring pixel-level pitch-matched transmit beamforming circuits which support arbitrary pulse duration. Our direct integration method enabled up to 10 MHz ultrasound arrays in a patch form-factor, leading to focal spot diameter of ∼200 μm, while pixel pitch-matched beamforming allowed for precise three-dimensional positioning of the ultrasound focal spot. Our device has the potential to provide a high-spatial resolution and wearable interface to both powering of highly-miniaturized implantable devices and ultrasound neuromodulation.

There has been increasing interest in wireless, miniaturized implantable medical devices for in vivo and in situ physiological monitoring. Here, we present such an implant that uses a conventional ultrasound imager for wireless powering and data communication and acts as a probe for real-time temperature sensing, including the monitoring of body temperature and temperature changes resulting from therapeutic application of ultrasound. The sub-0.1-mm 3 , sub-1-nW device, referred to as a mote, achieves aggressive miniaturization through the monolithic integration of a custom low-power temperature sensor chip with a microscale piezoelectric transducer fabricated on top of the chip. The small displaced volume of these motes allows them to be implanted or injected using minimally invasive techniques with improved biocompatibility. We demonstrate their sensing functionality in vivo for an ultrasound neurostimulation procedure in mice. Our motes have the potential to be adapted to the distributed and localized sensing of other clinically relevant physiological parameters., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Electron beam lithography (EBL) is the state-of-the-art technique for rapid prototyping of nanometer-scale devices. Even so, processing speeds remain limited for the highest resolution patterning. Here, we establish Mr-EBL as the highest throughput negative tone electron-beam-sensitive resist. The 10 μ C cm -2 dose requirement enables fabricating a 100 mm 2 photonic diffraction grating in a ten minute EBL process. Optimized processing conditions achieve a critical resolution of 75 nm with 3× faster write speeds than SU-8 and 1-2 orders of magnitude faster write speeds than maN-2400 and hydrogen silsesquioxane. Notably, these conditions significantly differ from the manufacturers' recommendations for the recently commercialized Mr-EBL resist. We demonstrate Mr-EBL to be a robust negative etch mask by etching silicon trenches with aspect ratios of 10 and near-vertical sidewalls. Furthermore, our optimized processing conditions are suitable to direct patterning on integrated circuits or delicate nanofabrication stacks, in contrast to other negative tone EBL resists. In conclusion, Mr-EBL is a highly attractive EBL resist for rapid prototyping in nanophotonics, MEMS, and fluidics., (© 2021 IOP Publishing Ltd.)

There is growing interest in integrating piezoelectric materials with complementary metal-oxide-semiconductor (CMOS) technology to enable expanded applications. A promising material for ultrasound transducer applications is polyvinylidene fluoride (PVDF), a piezoelectric polymer. One of the challenges with PVDF is that its piezoelectric properties can deteriorate when exposed to temperatures in excess of 70 °C for extended periods of time during fabrication. Here, we report on the effects of both shortening annealing times and providing this heating non-uniformly, as is characteristic of some processing conditions, on the piezoelectric coefficient ( d 33 ) of PVDF films for various thicknesses. In this case, no degradation in the d 33 was observed at temperatures below 100 °C for anneal times of under one minute when this heating is applied through one side of the film, making PVDF compatible with many bonding and photolithographic processing steps required for CMOS integration. More surprisingly, for one-sided heating to temperatures between 90 °C and 110 °C, we observed a transient enhancement of the d 33 by nearly 40% that lasted for several hours after these anneals. We attribute this effect to induced strain in these films.

We propose a new paradigm for dense functional imaging of brain activity to surmount the limitations of present methodologies. We term this approach "integrated neurophotonics"; it combines recent advances in microchip-based integrated photonic and electronic circuitry with those from optogenetics. This approach has the potential to enable lens-less functional imaging from within the brain itself to achieve dense, large-scale stimulation and recording of brain activity with cellular resolution at arbitrary depths. We perform a computational study of several prototype 3D architectures for implantable probe-array modules that are designed to provide fast and dense single-cell resolution (e.g., within a 1-mm 3 volume of mouse cortex comprising ∼100,000 neurons). We describe progress toward realizing integrated neurophotonic imaging modules, which can be produced en masse with current semiconductor foundry protocols for chip manufacturing. Implantation of multiple modules can cover extended brain regions., Competing Interests: Declaration of Interests Three patents owned by the California Institute of Technology have been pursued in connection with this work: (1) Roukes (2011). Brain-machine interface based on photonic neural probe arrays. U.S.P.T.O. Patent No. 10,638,933, Issued May 5, 2020, Priority Date: December 8, 2011. (2) Segev, E., Moreaux, L.C., Fowler, T.M. Faraon, A., Roukes, M.L. Implantable, highly collimated light-emitters for biological applications. U.S.P.T.O. Patent No. 10,471,273, Issue date: 12 November 2019; Priority date: 16 October 2015. (3) Roukes et al. (2016). One-photon integrated neurophotonic systems. U.S.P.T.O. Patent Application 20160150963, Filing date: November 5, 2014; Publication date: June 2, 2016., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This paper presents a device for time-gated fluorescence imaging in the deep brain, consisting of two on-chip laser diodes and 512 single-photon avalanche diodes (SPADs). The edge-emitting laser diodes deliver fluorescence excitation above the SPAD array, parallel to the imager. In the time domain, laser diode illumination is pulsed and the SPAD is time-gated, allowing a fluorescence excitation rejection up to O.D. 3 at 1 ns of time-gate delay. Each SPAD pixel is masked with Talbot gratings to enable the mapping of 2D array photon counts into a 3D image. The 3D image achieves a resolution of 40, 35, and 73 μm in the x, y, and z directions, respectively, in a noiseless environment, with a maximum frame rate of 50 kilo-frames-per-second. We present measurement results of the spatial and temporal profiles of the dual-pulsed laser diode illumination and of the photon detection characteristics of the SPAD array. Finally, we show the imager's ability to resolve a glass micropipette filled with red fluorescent microspheres. The system's 420 μm-wide cross section allows it to be inserted at arbitrary depths of the brain while achieving a field of view four times larger than fiber endoscopes of equal diameter.

Accurate monitoring of physiological temperature is important for many biomedical applications, including monitoring of core body temperature, detecting tissue pathologies, and evaluating surgical procedures involving thermal treatment such as hyperthermia therapy and tissue ablation. Many of these applications can benefit from replacing external temperature probes with injectable wireless devices. Here we present such a device for real-time in vivo temperature monitoring that relies on "chip-as-system" integration. With an on-chip piezoelectric transducer and measuring only 380 μm × 300 μm × 570 μm, the 0.065-mm 3 monolithic device, in the form of a mote, harvests ultrasound energy for power and transmits temperature data through acoustic backscattering. Containing a low-power temperature sensor implemented with a subthreshold oscillator and consuming 0.813 nW at 37 °C, the mote achieves line sensitivity of 0.088 °C/V, temperature error of +0.22/-0.28 °C, and a resolution of 0.0078 °C rms. A long-term measurement with the mote reveals an Allan deviation floor of <138.6 ppm, indicating the feasibility of using the mote for continuous physiological temperature monitoring.

Microbes living in biofilms, dense assemblages of cells, experience limitation for resources such as oxygen when cellular consumption outpaces diffusion. The pathogenic bacterium Pseudomonas aeruginosa has strategies for coping with hypoxia that support cellular redox balancing in biofilms; these include (1) increasing access to oxygen by forming wrinkles in the biofilm surface and (2) electrochemically reducing endogenous compounds called phenazines, which can shuttle electrons to oxidants available at a distance. Phenazine-mediated extracellular electron transfer (EET) has been shown to support survival for P. aeruginosa cells in anoxic liquid cultures, but the physiological relevance of EET over a distance for P. aeruginosa biofilms has remained unconfirmed. Here, we use a custom-built electrochemistry setup to show that phenazine-mediated electron transfer at a distance inhibits wrinkle formation in P. aeruginosa biofilms. This result demonstrates that phenazine-dependent EET to a distal oxidant affects biofilm morphogenesis., Competing Interests: The authors of this manuscript declare no conflict of interest., (© 2020 The Authors.)

This paper describes an inductively powered 27-Mbps, 0.08-mm 3 CMOS transceiver with integrated RF receiver coils for simultaneous two-way, near-field data telemetry and power transmission for implantable systems. A four-coil inductive link operates at a 27-MHz carrier for power and a 700-MHz carrier for data telemetry with the antennae taking an area of only 2 mm by 2 mm. Amplitude-shift-keying (ASK) modulation is used for data downlink at 6.6 kbps and load-shift keying (LSK) backscattering is used for data uplink at 27 Mbps. The transceiver consumes 2.7 mW and can power a load consuming up to an additional 1.5 mW. Implemented in a 0.18-um silicon-on-insulator (SOI) technology, post-processing steps are used to decrease chip thickness to approximately 15um, making the chip flexible with a tissue-like form factor and removing the effects of the substrate on coil performance. Power harvesting circuitry, including passive rectifier, voltage regulator, RF limiter, ASK and LSK modulator, clock generator, and digital controller are positioned adjacent to the coils and limited to an area of 0.5 mm by 2mm. Complete transceiver functionality of the system has been achieved with overall power transfer efficiency (PTE) of 1.04% through 1 mm of tissue phantom between reader and implant.

Single-walled carbon nanotubes (SWCNTs) are well-established transporters of electronic current, electrolyte, and ions. In this work, we demonstrate an electrically actuated biomimetic ion pump by combining these electronic and nanofluidic transport capabilities within an individual SWCNT device. Ion pumping is driven by a solid-state electronic input, as Coulomb drag coupling transduces electrical energy from solid-state charge along the SWCNT shell to electrolyte inside the SWCNT core. Short-circuit ionic currents, measured without an electrolyte potential difference, exceed 1 nA and scale larger with increasing ion concentrations through 1 M, demonstrating applicability under physiological (∼140 mM) and saltwater (∼600 mM) conditions. The interlayer coupling allows ionic currents to be tuned with the source-drain potential difference and electronic currents to be tuned with the electrolyte potential difference. This combined electronic-nanofluidic SWCNT device presents intriguing applications as a biomimetic ion pump or component of an artificial membrane.

We present an implantable single photon shank-based imager, monolithically integrated onto a single CMOS IC. The imager comprises of 512 single photon avalanche diodes distributed along two shanks, with a 6-bit depth in-pixel memory and an on-chip digital-to-time converter. To scale down the system to a minimally invasive form factor, we substitute optical filtering and focusing elements with a time-gated, angle-sensitive detection system. The imager computationally reconstructs the position of fluorescent sources within a three-dimensional volume of 3.4 mm × 600 µ m × 400 µ m.

Ion current rectification (ICR) is a transport phenomenon in which an electrolyte conducts unequal currents at equal and opposite voltages. Here, we show that nanoscale fluid vortices and nonlinear electroosmotic flow (EOF) drive ICR in the presence of concentration gradients. The same EOF can yield negative differential resistance (NDR), in which current decreases with increasing voltage. A finite element model quantitatively reproduces experimental ICR and NDR recorded across glass nanopipettes under concentration gradients. The model demonstrates that spatial variations of electrical double layer properties induce the nanoscale vortices and nonlinear EOF. Experiments are performed in conditions directly related to scanning probe imaging and show that quantitative understanding of nanoscale transport under concentration gradients requires accounting for EOF. This characterization of nanopipette transport physics will benefit diverse experimentation, pushing the resolution limits of chemical and biophysical recordings.

Accurate and low-cost analysis of biomolecules is important for many applications. This work seeks to further improve the measurement bandwidths achievable with solid-state nanopores, which have emerged as an important platform for this analysis. We report single-stranded DNA translocation recordings at a bandwidth of 10 MHz copolymers of 80 (C 20 A 20 C 20 A 20 ), 90 (C 30 A 30 C 30 ), and 200 (C 50 A 50 C 50 A 50 ) nucleotides through Si nanopores with effective diameters of 1.4-2.1 nm and effective membrane thicknesses 0.5-8.9 nm. By optimizing glass chips with thin nanopores and by integrating them with custom-designed amplifiers based on complementary metal-oxide-semiconductor technology, this work demonstrates detection of translocation events as brief as 100 ns with a signal-to-noise ratio exceeding seven at a measurement bandwidth of 10 MHz. We also report data robustness and variability across 13 pores of similar size and thickness, yielding a current blockade between 30 and 60% with a mean ionic current blockade (Δ I ) of ∼3-9 nA and a characteristic dwell time of ∼2-21 ns per nucleotide. These measurements show that characteristic translocation rates are at least 10 times faster than previously recorded. We detect transient intraevent fluctuations, multiple current levels within translocation events, and variability of DNA translocation event signatures and durations.

Intracellular electrophysiology is a foundational method in neuroscience and uses electrolyte-filled glass electrodes and benchtop amplifiers to measure and control transmembrane voltages and currents. Commercial amplifiers perform such recordings with high signal-to-noise ratios (SNRs) but are often expensive, bulky, and not easily scalable to many channels due to reliance on board-level integration of discrete components. Here, we present a monolithic complementary-metal-oxide-semiconductor (CMOS) multi-clamp amplifier integrated circuit capable of recording both voltages and currents with performance exceeding that of commercial benchtop instrumentation. Miniaturization enables high-bandwidth current mirroring, facilitating the synthesis of large-valued active resistors with lower noise than their passive equivalents. This enables the realization of compensation modules that can account for a wide range of electrode impedances. We validate the amplifier's operation electrically, in primary neuronal cultures, and in acute slices, using both high-impedance sharp and patch electrodes. This work provides a solution for low-cost, high-performance and scalable multi-clamp amplifiers., Competing Interests: CONFLICT OF INTEREST S.S., K.J. and K.L.S. are listed as inventors on a provisional patent filed by Columbia University.

Transport processes through ion-channel proteins, protein pores, or solid-state nanopores are traditionally recorded with commercial patch-clamp amplifiers. The bandwidth of these systems is typically limited to 10 kHz by signal-to-noise-ratio (SNR) considerations associated with these measurement platforms. At high bandwidth, the input-referred current noise in these systems dominates, determined by the input-referred voltage noise of the transimpedance amplifier applied across the capacitance at the input of the amplifier. This capacitance arises from several sources: the parasitic capacitance of the amplifier itself; the capacitance of the lipid bilayer harboring the ion channel protein (or the membrane used to form the solid-state nanopore); and the capacitance from the interconnections between the electronics and the membrane. Here, we review state-of-the-art applications of high-bandwidth conductance recordings of both ion channels and solid-state nanopores. These approaches involve tightly integrating measurement electronics fabricated in complementary metal-oxide semiconductors (CMOS) technology with lipid bilayer or solid-state membranes. SNR improvements associated with this tight integration push the limits of measurement bandwidths, in some cases in excess of 10 MHz. Recent case studies demonstrate the utility of these approaches for DNA sequencing and ion-channel recordings. In the latter case, studies with extended bandwidth have shown the potential for providing new insights into structure-function relations of these ion-channel proteins as the temporal resolutions of functional recordings matches time scales achievable with state-of-the-art molecular dynamics simulations., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Recent work has pushed the noise-limited bandwidths of solid-state nanopore conductance recordings to more than 5 MHz and of ion channel conductance recordings to more than 500 kHz through the use of integrated complementary metal-oxide-semiconductor (CMOS) integrated circuits. Despite the spectral spread of the pulse-like signals that characterize these recordings when a sinusoidal basis is employed, Bessel filters are commonly used to denoise these signals to acceptable signal-to-noise ratios (SNRs) at the cost of losing many of the faster temporal features. Here, we report improvements to the SNR that can be achieved using wavelet denoising instead of Bessel filtering. When combined with state-of-the-art high-bandwidth CMOS recording instrumentation, we can reduce baseline noise levels by over a factor of 4 compared to a 2.5 MHz Bessel filter while retaining transient properties in the signal comparable to this filter bandwidth. Similarly, for ion-channel recordings, we achieve a temporal response better than a 100 kHz Bessel filter with a noise level comparable to that achievable with a 25 kHz Bessel filter. Improvements in SNR can be used to achieve robust statistical analyses of these recordings, which may provide important insights into nanopore translocation dynamics and mechanisms of ion-channel function.

Intracellular recordings in vivo remains the best technique to link single-neuron electrical properties to network function. Yet existing methods are limited in accuracy, throughput, and duration, primarily via washout, membrane damage, and movement-induced failure. Here, we introduce flexible quartz nanopipettes (inner diameters of 10-25 nm and spring constant of ∼0.08 N/m) as nanoscale analogs of traditional glass microelectrodes. Nanopipettes enable stable intracellular recordings (seal resistances of 500 to ∼800 MΩ, 5 to ∼10 cells/nanopipette, and duration of ∼1 hr) in anaesthetized and awake head-restrained mice, exhibit minimal diffusional flux, and facilitate precise recording and stimulation. When combined with quantum-dot labels and microprisms, nanopipettes enable two-photon targeted electrophysiology from both somata and dendrites, and even paired recordings from neighboring neurons, while permitting simultaneous population imaging across cortical layers. We demonstrate the versatility of this method by recording from parvalbumin-positive (Pv) interneurons while imaging seizure propagation, and we find that Pv depolarization block coincides with epileptic spread. Flexible nanopipettes present a simple method to procure stable intracellular recordings in vivo., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Advances in sensing technology raise the possibility of creating neural interfaces that can more effectively restore or repair neural function and reveal fundamental properties of neural information processing. To realize the potential of these bioelectronic devices, it is necessary to understand the capabilities of emerging technologies and identify the best strategies to translate these technologies into products and therapies that will improve the lives of patients with neurological and other disorders. Here we discuss emerging technologies for sensing brain activity, anticipated challenges for translation, and perspectives for how to best transition these technologies from academic research labs to useful products for neuroscience researchers and human patients.

Single-point-functionalized carbon-nanotube field-effect transistors (CNTFETs) have been used to sense conformational changes and binding events in protein and nucleic acid structures from intrinsic molecular charge. The key to utilizing these devices as single-molecule sensors is the ability to attach a single probe molecule to an individual device. In contrast, with noncovalent attachment approaches such as those based on van der Waals interactions, covalent attachment approaches generally deliver higher stability but have traditionally been more difficult to control, resulting in low yield. Here, we present a single-point-functionalization method for CNTFET arrays based on electrochemical control of a diazonium reaction to create sp 3 defects, combined with a scalable spin-casting method for fabricating large arrays of devices on arbitrary substrates.  Attachment of probe DNA to the functionalized device enables single-molecule detection of DNA hybridization with complementary target, verifying the single-point functionalization. Overall, this method enables single-point defect generation with 80% yield.

Presents corrections to the paper, "Statistically reconstructed multiplexing for very dense, high-channel-count acquisition systems," (Tsai, D., et al), IEEE Trans. Biomed. Circuits Syst., vol. 8, no. 1, pp. 13-23, Feb. 2018.

In this work, we present a CMOS-integrated low-noise junction field-effect transistor (JFET) developed in a standard 0.18 pm CMOS process. These JFETs reduce input-referred flicker noise power by more than a factor of 10 when compared to equally sized n-channel MOS devices by eliminating oxide interfaces in contact with the channel. We show that this improvement in device performance translates into a factor-of-10 reduction in the input-referred noise of integrated CMOS operational amplifiers when JFET devices are used at the input, significant for many applications in bioelectronics.

Single-channel recordings are widely used to explore functional properties of ion channels. Typically, such recordings are performed at bandwidths of less than 10 kHz because of signal-to-noise considerations, limiting the temporal resolution available for studying fast gating dynamics to greater than 100 µs. Here we present experimental methods that directly integrate suspended lipid bilayers with high-bandwidth, low-noise transimpedance amplifiers based on complementary metal-oxide-semiconductor (CMOS) integrated circuits (IC) technology to achieve bandwidths in excess of 500 kHz and microsecond temporal resolution. We use this CMOS-integrated bilayer system to study the type 1 ryanodine receptor (RyR1), a Ca 2+ -activated intracellular Ca 2+ -release channel located on the sarcoplasmic reticulum. We are able to distinguish multiple closed states not evident with lower bandwidth recordings, suggesting the presence of an additional Ca 2+ binding site, distinct from the site responsible for activation. An extended beta distribution analysis of our high-bandwidth data can be used to infer closed state flicker events as fast as 35 ns. These events are in the range of single-file ion translocations., Competing Interests: Conflict of interest statement: A.R.M. is a consultant and member of the board and chair of the scientific advisory board of ARMGO Pharma and owns shares in the company that is targeting RyR channels for therapeutic purposes.

Ultrafast electrically driven nanoscale light sources are critical components in nanophotonics. Compound semiconductor-based light sources for the nanophotonic platforms have been extensively investigated over the past decades. However, monolithic ultrafast light sources with a small footprint remain a challenge. Here, we demonstrate electrically driven ultrafast graphene light emitters that achieve light pulse generation with up to 10 GHz bandwidth across a broad spectral range from the visible to the near-infrared. The fast response results from ultrafast charge-carrier dynamics in graphene and weak electron-acoustic phonon-mediated coupling between the electronic and lattice degrees of freedom. We also find that encapsulating graphene with hexagonal boron nitride (hBN) layers strongly modifies the emission spectrum by changing the local optical density of states, thus providing up to 460% enhancement compared to the gray-body thermal radiation for a broad peak centered at 720 nm. Furthermore, the hBN encapsulation layers permit stable and bright visible thermal radiation with electronic temperatures up to 2000 K under ambient conditions as well as efficient ultrafast electronic cooling via near-field coupling to hybrid polaritonic modes under electrical excitation. These high-speed graphene light emitters provide a promising path for on-chip light sources for optical communications and other optoelectronic applications.

Multiplexing is an important strategy in multichannel acquisition systems. The per-channel antialiasing filters needed in the traditional multiplexing architecture limit its scalability for applications requiring high channel density, high channel count, and low noise. A particularly challenging example is multielectrode arrays for recording from neural systems. We show that conventional approaches must tradeoff recording density and noise performance, at a scale far from the ideal goal of one-to-one mapping between neurons and sensors. We present a multiplexing architecture without per-channel antialiasing filters. The sparsely sampled data are recovered through a compressed sensing strategy, involving statistical reconstruction and removal of the undersampled thermal noise. In doing so, we replace large analog components with digital signal processing blocks, which are much more amenable to scaled CMOS implementation. The resulting statistically reconstructed multiplexing architecture recovers input signals at significantly improved signal-to-noise ratios when compared to conventional multiplexing with antialiasing filters at the same per-channel area. We implement the new architecture in a 65 536-channel neural recording system and show that it is able to recover signals with performance comparable to conventional high-performance, single-channel systems, despite a more than four-orders-of-magnitude increase in channel density.

Lipid bilayers provide many benefits for ion channel recordings, such as control of membrane composition and transport molecules. However, they suffer from high membrane capacitance limiting the bandwidth and impeding analysis of fast gating. This can be overcome by fitting the deviations of the open-channel noise from the baseline noise by extended beta distributions. We demonstrate this analysis step-by-step by applying it to the example of viral K +  channels (Kcv), from the choice of the gating model through the fitting process, validation of the results, and what kinds of results can be obtained. These voltage sensor-less channels show profoundly voltage-dependent gating with dwell times in the closed state of about 50 μs. Mutations assign it to the selectivity filter., (© 2017 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

In traditional electrophysiology, spatially inefficient electronics and the need for tissue-to-electrode proximity defy non-invasive interfaces at scales of more than a thousand low noise, simultaneously recording channels. Using compressed sensing concepts and silicon complementary metal-oxide-semiconductors (CMOS), we demonstrate a platform with 65,536 simultaneously recording and stimulating electrodes in which the per-electrode electronics consume an area of 25.5 μm by 25.5 μm. Application of this platform to mouse retinal studies is achieved with a high-performance processing pipeline with a 1 GB/s data rate. The platform records from 65,536 electrodes concurrently with a ~10 µV r.m.s. noise; senses spikes from more than 34,000 electrodes when recording across the entire retina; automatically sorts and classifies greater than 1700 neurons following visual stimulation; and stimulates individual neurons using any number of the 65,536 electrodes while observing spikes over the entire retina. The approaches developed here are applicable to other electrophysiological systems and electrode configurations.

The study of biomolecular interactions at the single-molecule level holds great potential for both basic science and biotechnology applications. Single-molecule studies often rely on fluorescence-based reporting, with signal levels limited by photon emission from single optical reporters. The point-functionalized carbon nanotube transistor, known as the single-molecule field-effect transistor, is a bioelectronics alternative based on intrinsic molecular charge that offers significantly higher signal levels for detection. Such devices are effective for characterizing DNA hybridization kinetics and thermodynamics and enabling emerging applications in genomic identification. In this work, we show that hybridization kinetics can be directly controlled by electrostatic bias applied between the device and the surrounding electrolyte. We perform the first single-molecule experiments demonstrating the use of electrostatics to control molecular binding. Using bias as a proxy for temperature, we demonstrate the feasibility of detecting various concentrations of 20-nt target sequences from the Ebolavirus nucleoprotein gene in a constant-temperature environment.