Magnetoelectric Bio-Implants Powered and Programmed by a Single Transmitter for Coordinated Multisite Stimulation.

This paper presents a hardware platform including stimulating implants wirelessly powered and controlled by a shared transmitter for coordinated leadless multisite stimulation. The adopted novel single-transmitter, multiple-implant structure can flexibly deploy stimuli, improve system efficiency, easily scale stimulating channel quantity and relieve efforts in device synchronization. In the proposed system, a wireless link leveraging magnetoelectric effects is co-designed with a robust and efficient system-on-chip to enable reliable operation and individual programming of every implant. Each implant integrates a 0.8-mm2 chip, a 6-mm2 magnetoelectric film, and an energy storage capacitor within a 6.2-mm3 size. Magnetoelectric power transfer is capable of safely transmitting milliwatt power to devices placed several centimeters away from the transmitter coil, maintaining good efficiency with size constraints and tolerating 60-degree, 1.5-cm misalignment in angular and lateral movement. The SoC robustly operates with 2-V source amplitude variations that spans a 40-mm transmitter-implant distance change, realizes individual addressability through physical unclonable function IDs, and achieves 90% efficiency for 1.5-to-3.5-V stimulation with fully programmable stimulation parameters.

Magnetic Entropy as a Proposed Gating Mechanism for Magnetogenetic Ion Channels.

Magnetically sensitive ion channels would allow researchers to better study how specific brain cells affect behavior in freely moving animals; however, recent reports of "magnetogenetic" ion channels based on biogenic ferritin nanoparticles have been questioned because known biophysical mechanisms cannot explain experimental observations. Here, we reproduce a weak magnetically mediated calcium response in HEK cells expressing a previously published TRPV4-ferritin fusion protein. We find that this magnetic sensitivity is attenuated when we reduce the temperature sensitivity of the channel but not when we reduce the mechanical sensitivity of the channel, suggesting that the magnetic sensitivity of this channel is thermally mediated. As a potential mechanism for this thermally mediated magnetic response, we propose that changes in the magnetic entropy of the ferritin particle can generate heat via the magnetocaloric effect and consequently gate the associated temperature-sensitive ion channel. Unlike other forms of magnetic heating, the magnetocaloric mechanism can cool magnetic particles during demagnetization. To test this prediction, we constructed a magnetogenetic channel based on the cold-sensitive TRPM8 channel. Our observation of a magnetic response in cold-gated channels is consistent with the magnetocaloric hypothesis. Together, these new data and our proposed mechanism of action provide additional resources for understanding how ion channels could be activated by low-frequency magnetic fields.

Integrated light-sheet illumination using metallic slit microlenses.

Light sheet microscopy (LSM) - also known as selective plane illumination microscopy (SPIM) - enables high-speed, volumetric imaging by illuminating a two-dimensional cross-section of a specimen. Typically, this light sheet is created by table-top optics, which limits the ability to miniaturize the overall SPIM system. Replacing this table-top illumination system with miniature, integrated devices would reduce the cost and footprint of SPIM systems. One important element for a miniature SPIM system is a flat, easily manufactured lens that can form a light sheet. Here we investigate planar metallic lenses as the beam shaping element of an integrated SPIM illuminator. Based on finite difference time domain (FDTD) simulations, we find that diffraction from a single slit can create planar illumination with a higher light throughput than zone plate or plasmonic lenses. Metallic slit microlenses also show broadband operation across the entire visible range and are nearly polarization insensitive. Furthermore, compared to meta-lenses based on sub-wavelength-scale diffractive elements, metallic slit lenses have micron-scale features compatible with low-cost photolithographic manufacturing. These features allow us to create inexpensive integrated devices that generate light-sheet illumination comparable to tabletop microscopy systems. Further miniaturization of this type of integrated SPIM illuminators will open new avenues for flat, implantable photonic devices for in vivo biological imaging.

Hydra vulgaris shows stable responses to thermal stimulation despite large changes in the number of neurons.

Many animals that lose neural tissue to injury or disease can maintain behavioral repertoires by regenerating new neurons or reorganizing existing neural circuits. However, most neuroscience small model organisms lack this high degree of neural plasticity. We show that Hydra vulgaris can maintain stable sensory-motor behaviors despite 2-fold changes in neuron count, due to naturally occurring size variation or surgical resection. Specifically, we find that both behavioral and neural responses to rapid temperature changes are maintained following these perturbations. We further describe possible mechanisms for the observed neural activity and argue that Hydra's radial symmetry may allow it to maintain stable behaviors when changes in the numbers of neurons do not selectively eliminate any specific neuronal cell type. These results suggest that Hydra provides a powerful model for studying how animals maintain stable sensory-motor responses within dynamic neural circuits and may lead to the development of general principles for injury-tolerant neural architectures.

Wearable wireless power systems for 'ME-BIT' magnetoelectric-powered bio implants.

Objective.Compared to biomedical devices with implanted batteries, wirelessly powered technologies can be longer-lasting, less invasive, safer, and can be miniaturized to access difficult-to-reach areas of the body. Magnetic fields are an attractive wireless power transfer modality for such bioelectronic applications because they suffer negligible absorption and reflection in biological tissues. However, current solutions using magnetic fields for mm sized implants either operate at high frequencies (>500 kHz) or require high magnetic field strengths (>10 mT), which restricts the amount of power that can be transferred safely through tissue and limits the development of wearable power transmitter systems. Magnetoelectric (ME) materials have recently been shown to provide a wireless power solution for mm-sized neural stimulators. These ME transducers convert low magnitude (<1 mT) and low-frequency (∼300 kHz) magnetic fields into electric fields that can power custom integrated circuits or stimulate nearby tissue.Approach.Here we demonstrate a battery-powered wearable magnetic field generator that can power a miniaturized MagnetoElectric-powered Bio ImplanT 'ME-BIT' that functions as a neural stimulator. The wearable transmitter weighs less than 0.5 lbs and has an approximate battery life of 37 h.Main results.We demonstrate the ability to power a millimeter-sized prototype 'ME-BIT' at a distance of 4 cm with enough energy to electrically stimulate a rat sciatic nerve. We also find that the system performs well under translational misalignment and identify safe operating ranges according to the specific absorption rate limits set by the IEEE Std 95.1-2019.Significance.These results validate the feasibility of a wearable system that can power miniaturized ME implants that can be used for different neuromodulation applications.

Bioelectronics for Millimeter-Sized Model Organisms.

Advances in microfabrication technologies and biomaterials have enabled a growing class of electronic devices that can stimulate and record bioelectronic signals. Many of these devices have been developed for humans or vertebrate animals, where miniaturization allows for implantation within the body. There are, however, another class of bioelectronic interfaces that exploit microfabrication and nanoelectronics to record signals from tiny, millimeter-sized organisms. In these cases, rather than implanting a device inside an animal, animals themselves are loaded in large numbers into bioelectronic devices for neural circuit and behavioral interrogation. These scalable interfaces provide platforms to develop new therapeutics as well as better understand basic principles of bioelectronic communication, neuroscience, and behavior. Here we review recent progress in these bioelectronic technologies and describe how they can complement on-chip optical, mechanical, and chemical interrogation methods to achieve high-throughput, multimodal studies of millimeter-sized small animals.

MagNI: A Magnetoelectrically Powered and Controlled Wireless Neurostimulating Implant.

This paper presents the first wireless and programmable neural stimulator leveraging magnetoelectric (ME) effects for power and data transfer. Thanks to low tissue absorption, low misalignment sensitivity and high power transfer efficiency, the ME effect enables safe delivery of high power levels (a few milliwatts) at low resonant frequencies (  âˆ¼ 250 kHz) to mm-sized implants deep inside the body (30-mm depth). The presented MagNI (Magnetoelectric Neural Implant) consists of a 1.5-mm 2 180-nm CMOS chip, an in-house built 4 × 2 mm ME film, an energy storage capacitor, and on-board electrodes on a flexible polyimide substrate with a total volume of 8.2 mm 3. The chip with a power consumption of 23.7  µW includes robust system control and data recovery mechanisms under source amplitude variations (1-V variation tolerance). The system delivers fully-programmable bi-phasic current-controlled stimulation with patterns covering 0.05-to-1.5-mA amplitude, 64-to-512- µs pulse width, and 0-to-200-Hz repetition frequency for neurostimulation.

Microfluidics for electrophysiology, imaging, and behavioral analysis of Hydra.

The nervous system of the cnidarian Hydra vulgaris exhibits remarkable regenerative abilities. When cut in two, the bisected tissue reorganizes into fully behaving animals in approximately 48 hours. Furthermore, new animals can reform from aggregates of dissociated cells. Understanding how behaviors are coordinated by this highly plastic nervous system could reveal basic principles of neural circuit dynamics underlying behaviors. However, Hydra's deformable and contractile body makes it difficult to manipulate the local environment while recording neural activity. Here, we present the first microfluidic technologies capable of simultaneous electrical, chemical, and optical interrogation of these soft, deformable organisms. Specifically, we demonstrate devices that can immobilize Hydra for hours-long simultaneous electrical and optical recording, and chemical stimulation of behaviors revealing neural activity during muscle contraction. We further demonstrate quantitative locomotive and behavioral tracking made possible by confining the animal to quasi-two-dimensional micro-arenas. Together, these proof-of-concept devices show that microfluidics provide a platform for scalable, quantitative cnidarian neurobiology. The experiments enabled by this technology may help reveal how highly plastic networks of neurons provide robust control of animal behavior.

Single-frame 3D fluorescence microscopy with ultraminiature lensless FlatScope.

Modern biology increasingly relies on fluorescence microscopy, which is driving demand for smaller, lighter, and cheaper microscopes. However, traditional microscope architectures suffer from a fundamental trade-off: As lenses become smaller, they must either collect less light or image a smaller field of view. To break this fundamental trade-off between device size and performance, we present a new concept for three-dimensional (3D) fluorescence imaging that replaces lenses with an optimized amplitude mask placed a few hundred micrometers above the sensor and an efficient algorithm that can convert a single frame of captured sensor data into high-resolution 3D images. The result is FlatScope: perhaps the world's tiniest and lightest microscope. FlatScope is a lensless microscope that is scarcely larger than an image sensor (roughly 0.2 g in weight and less than 1 mm thick) and yet able to produce micrometer-resolution, high-frame rate, 3D fluorescence movies covering a total volume of several cubic millimeters. The ability of FlatScope to reconstruct full 3D images from a single frame of captured sensor data allows us to image 3D volumes roughly 40,000 times faster than a laser scanning confocal microscope while providing comparable resolution. We envision that this new flat fluorescence microscopy paradigm will lead to implantable endoscopes that minimize tissue damage, arrays of imagers that cover large areas, and bendable, flexible microscopes that conform to complex topographies.

Scalable electrophysiology in intact small animals with nanoscale suspended electrode arrays.

Electrical measurements from large populations of animals would help reveal fundamental properties of the nervous system and neurological diseases. Small invertebrates are ideal for these large-scale studies; however, patch-clamp electrophysiology in microscopic animals typically requires invasive dissections and is low-throughput. To overcome these limitations, we present nano-SPEARs: suspended electrodes integrated into a scalable microfluidic device. Using this technology, we have made the first extracellular recordings of body-wall muscle electrophysiology inside an intact roundworm, Caenorhabditis elegans. We can also use nano-SPEARs to record from multiple animals in parallel and even from other species, such as Hydra littoralis. Furthermore, we use nano-SPEARs to establish the first electrophysiological phenotypes for C. elegans models for amyotrophic lateral sclerosis and Parkinson's disease, and show a partial rescue of the Parkinson's phenotype through drug treatment. These results demonstrate that nano-SPEARs provide the core technology for microchips that enable scalable, in vivo studies of neurobiology and neurological diseases.

NeuroPG: open source software for optical pattern generation and data acquisition.

Patterned illumination using a digital micromirror device (DMD) is a powerful tool for optogenetics. Compared to a scanning laser, DMDs are inexpensive and can easily create complex illumination patterns. Combining these complex spatiotemporal illumination patterns with optogenetics allows DMD-equipped microscopes to probe neural circuits by selectively manipulating the activity of many individual cells or many subcellular regions at the same time. To use DMDs to study neural activity, scientists must develop specialized software to coordinate optical stimulation patterns with the acquisition of electrophysiological and fluorescence data. To meet this growing need we have developed an open source optical pattern generation software for neuroscience-NeuroPG-that combines, DMD control, sample visualization, and data acquisition in one application. Built on a MATLAB platform, NeuroPG can also process, analyze, and visualize data. The software is designed specifically for the Mightex Polygon400; however, as an open source package, NeuroPG can be modified to incorporate any data acquisition, imaging, or illumination equipment that is compatible with MATLAB's Data Acquisition and Image Acquisition toolboxes.