R-3 Repository :: Browsing by Author "Robinson, Jacob T"

Browsing by Author "Robinson, Jacob T"

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A Microfluidic Device for Sorting Cells According to Suspended Nanoelectrode Electrophysiology
(2017-08-14) Bell, Andrew; Robinson, Jacob T
Electrically active tissues and cells are found in all kingdoms of life and allow us to perceive, process, and impact our environment. Despite the ubiquity and importance of electrical activity in biology, the genes and proteins controlling many electrically dependent abilities remain incompletely characterized. Electrically excitable cells are highly specialized, frequently resulting in a high degree of heterogeneity, and when analyzing at a population level, the proteins or genes responsible for the behavior of a few cells are quickly drowned out. To facilitate separation of subpopulations of electrically active cells, we have designed, fabricated, and tested a device incorporating nanoelectrodes into a micro uidic chip for sorting cells based on their electrophysiology.
Accurate noninvasive monitoring of fetal tissue oxygenation level
(2024-04-01) Guo, Zijing; Robinson, Jacob T
Fetal blood oxygenation level serves as a critical indicator of fetal health throughout pregnancy and labor. However, existing clinical devices predominantly employ invasive techniques, posing risks to both the fetus and the mother. To address this concern, we present a noninvasive method for precise fetal oxygenation level monitoring using time-of-flight near-Infrared Spectroscopy (ToF-NIRS). Our method is the first to achieve accurate, multichannel signal separation from two distinct layers. We conducted Monte Carlo simulations and experiments on a fiber-based ToF-NIRS prototype. Our prototype system achieves <3% estimation error in a two-layer tissue phantom. Additionally, we perform in-vivo experiments to show that our system is able to detect reduced tissue oxygenation index (TOI) levels in a human arm, through a human tissue phantom, and can perform transabdominal fetal monitoring in living sheep. Our approach is a step towards reliable and noninvasive fetal oxygenation level monitoring in clinical settings.
Carbon Nanotube Fibers and Films as Bioelectronic Interfaces
(2020-04-24) Yan, Stephen; Pasquali, Matteo; Robinson, Jacob T
Carbon nanotubes (CNTs) have generated substantial research interests since their discovery in 1991. Individual CNTs possess exceptional mechanical (1000x strength of steel), electrical (almost 2x electrical conductivity of copper), and thermal (almost 2x thermal conductivity of diamond) properties, all at a fraction of the weight. As a result of these outstanding properties, CNTs are ideal candidates in applications such as sensors, energy storage and conversion, batteries, touch screen displays, field emitters, super capacitors, aerospace, wearables, biosensors, nanomedicine, and novel biomaterials. Early CNT applications use CNTs as individual molecules, coatings, or part of composites. With advancements in CNT processing, researchers have been able to fabricate CNTs into macroscopic 1D, 2D, and 3D objects with outstanding properties, such as CNT fibers (CNTFs), films, and foams. This thesis focuses on the biomedical applications of two such CNT macrostructures – CNTFs and CNT films. First, this thesis demonstrates in vivo restoration of myocardial conduction with CNTFs. Impaired myocardial conduction is the underlying mechanism for re-entrant arrhythmias. A restorative therapy had remained elusive due to the lack of biocompatible materials that restore myocardial conduction. CNTFs are uniquely suited to fill this need because they combine the mechanical properties of soft sutures with the conductive properties of metals. Here, by showing that CNTFs sewn across the mitral valve can create or restore conduction across anatomical barriers, we demonstrate CNTF to be a potential long-term restorative solution in pathologies interrupting efficient myocardial conduction. It is important to understand a material’s bio- and immune-compatibility profiles before it can be safely used as implanted bioelectronic interfaces. Therefore, the next part of this thesis systematically evaluates CNTF’s cellular, hematologic, immunologic, and organ compatibilities. Studies here show that 1) CNTF is biocompatible for both in vitro basic research and in vivo biomedical applications; 2) CNT macrostructures such as CNTF do not belong to the previously established “fiber pathogenicity paradigm” for CNTs. These results also establish baseline biocompatibility requirements for any future CNT-macrostructure-based bioelectronic interfaces. Finally, this thesis presents flexible and transparent neural electrode arrays made from CNT films for integrated optical and electrical investigations. These CNT electrodes are transparent, flexible, and possess low interface impedance. Their capacity to carry out integrated optical and electrical investigations is demonstrated through electrophysiological recording during concurrent calcium imaging in hydra.
Depth Limit of Imaging through Scattering Media using Selective Plane of Illumination Microscopy (SPIM)
(2015-12-03) Zhang, Shizheng; Veeraraghavan, Ashok; Robinson, Jacob T; Kemere, Caleb
In most biological tissues, the maximum optical imaging depth is limited by light scattering. Confocal and multi-photon microscopy have been developed to increase the imaging depth by limiting the amount of scattered light that reaches the detector, however, these techniques acquire images one point at a time resulting in reduced image acquisition speed. Recently, Selective Plane of Illumination Microscopy (SPIM) has emerged as an alternative 3D microscopy technique with faster image acquisition speeds, enabled by capturing entire 2D planes rather than individual points. While the advantages of SPIM for high speed imaging are understood, here we demonstrate that SPIM also increases the imaging depth in scattering media compared to confocal and epifluorescence techniques. We show both analytically and experimentally that SPIM can image 2-3 times deeper than confocal microscopy (~10x the mean scattering length). The primary reason for the deeper imaging capability of SPIM is the fact that off-axis illumination reduces the out-of-focus fluorescence above the imaging plane. We find that for scattering media, multi- photon microscopy can image deeper than SPIM; however, the fact that SPIM does not require a high-power pulsed laser makes this approach a lower cost alternative to multi-photon microscopy for imaging into scattering media beyond the depths of conventional single photon microscopy techniques.
EMvelop Stimulation: Minimally Invasive Deep Brain Stimulation using Temporally Interfering Electromagnetic Waves
(2024-04-18) Ahsan, Fatima; Aazhang, Behnaam; Robinson, Jacob T; Xie, Chong; Szablowski, Jerzy O
This thesis focuses on developing a novel brain stimulation methodology by using temporally interfering gigahertz (GHz) electromagnetic (EM) waves, termed EMvelop stimulation. Our work on EMvelop stimulation addresses two key aspects of developing this novel methodology: obtaining high electric field intensity and focality at target regions deep inside the brain tissue and fast and robust data-driven electric field estimation. First, we validate the idea of EMvelop stimulation using multi-physics modeling and algorithmic optimization simulations. We show that at GHz frequencies, we can create antenna arrays at the scale of a few centimeters or less that can be endocranially implanted to enable longitudinal stimulation and circumvent signal attenuation due to the scalp and skull. Furthermore, owing to the small wavelength of GHz EM waves, we can optimize both amplitudes and phases of the EM waves to achieve high intensity and focal stimulation at targeted regions. We develop a simulation framework investigating the propagation of GHz EM waves and the corresponding heat generated in the brain tissue. We propose two optimization flows to identify antenna current amplitudes and phases for either maximal intensity or maximal focality transmission of the interfering electric fields with EM waves safety constraint. A representative result of our study is that with two endocranially implanted arrays of size 4.2 cm x 4.7 cm each, we can achieve an intensity of 12 V/m with a focality of 3.6 cm at a target deep in the brain tissue. To the best of our knowledge, this is the first time the idea of EMvelop stimulation was proposed and investigated, and we demonstrated its benefits over prior methodologies of electrical stimulation. Second, a common factor across electromagnetic methodologies of brain stimulation is the optimization of essential dosimetry parameters, like amplitude, phase, and the location of one or more transducers, which controls the stimulation strength and targeting precision. Since obtaining in-vivo measurements for the electric field distribution inside the biological tissue is challenging, physics-based simulators are used. However, these physics-based simulators are computationally expensive and time-consuming, making computing the electric field repeatedly for optimization purposes computationally prohibitive. To overcome this issue, we trained a U-Net model using 14 segmented human magnetic resonance images (MRIs). Once trained, the model inputs a segmented human MRI and the antenna location and outputs the corresponding electric field. At 1.5 GHz, on the validation dataset consisting of 6 patients, we can estimate the electric field with the magnitude of complex correlation coefficient of 0.978. Additionally, we could calculate the electric field with a mean time of 4.4 ms for a potential antenna location. On average, this is at least 1200 times faster than the time required by state-of-the-art physics-based simulator COMSOL. The significance of this work is that it shows the possibility of real-time calculation of the electric field from the patient MRI and coordinates for the antenna, making it possible to optimize the amplitude, phase, and location of several different transducers with stochastic gradient descent since our model is a continuous function. Our work shows the potential of EMvelop stimulation to be portable, discreet, and continuously operable brain stimulation technology while being minimally invasive. The aim of our work is to expand the therapeutic options available to an even larger number of patients with neurological and psychiatric disorders.
In vivo Fluorescence Imaging with Lensless Microscopes
(2019-08-08) Adams, Jesse Kenneth; Robinson, Jacob T; Veeraraghavan, Ashok
Fluorescence microscopy is an essential tool for studying the brain. Not only can it provide sub-cellular information about brain structure, but it can also capture dynamic electrical and chemical activity from calcium- and voltage-sensitive indicators. An ideal fluorescence microscope would simultaneously image all the neurons in an animal with the temporal resolution to identify individual action potentials and would not restrict animal behavior. Unfortunately, lenses in traditional microscopes enforce a trade-off between size and weight, resolution, and field-of-view. It is not currently possible to simultaneously achieve cellular resolution, high frame rate, and large fields of view, with a small and lightweight microscope . Recent developments in computational imaging have made it possible to reconstruct images without the use of lenses , thus overcoming many constraints of traditional microscopy. Here we show the first demonstration of a lensless microscope that can perform structural and functional imaging of biological samples in vivo. Specifically, by replacing lenses with an optimized phase mask and computational image reconstruction algorithms we achieve cellular-resolution fluorescence imaging of fixed biological samples . We also demonstrate 2D and 3D in vivo imaging of neurons and muscle cells in millimeter-sized Hydra vulgaris, including measurement of dynamic calcium activity . Finally, we reconstruct stimulus-evoked calcium activity from neurons in mouse cortex . Further miniaturization of this lensless microscope by reducing the size of the electronic packaging will enable flat, and potentially fully implantable devices that can study neural activity over large areas of the brain as animals behave freely. We also anticipate that this new imaging capability can be used in other areas including endoscopy and point-of-care diagnostics, where the small form factor, large field of view, and high temporal resolution will provide advantages compared to current lens-based microscopes.
Interrogating Brain and Behavioral State Transitions with a Spontaneous C. elegans Sleep Behavior
(2019-04-17) Gonzales, Daniel L; Robinson, Jacob T
One remarkable feature of the nervous system is its ability to rapidly and spontaneously switch between activity states. In the extreme example of sleep, animals arrest locomotion, reduce their sensitivity to sensory stimuli, and dramatically alter their neural activity. Small organisms are useful models to better understand these sudden changes in neural states because we can simultaneously observe whole-brain activity, monitor behavior and precisely regulate the external environment. Here, we show a spontaneous sleep-like behavior in C. elegans, termed “μSleep,” that is associated with a distinct global-brain state and regulated by both the animal’s internal physiological state and input from multiple sensory circuits. Specifically, we found that when confined in microfluidic chambers, adult worms spontaneously transition between periods of normal activity and short quiescent bouts, with behavioral state transitions occurring every few minutes. This quiescent state, which we call μSleep, meets the behavioral requirements of C. elegans sleep, is dependent on known sleep-promoting neurons ALA and RIS, and is associated with a global down-regulation of neural activity. Consistent with prior studies of C. elegans sleep, we found that μSleep is regulated by satiety and temperature. In addition, we show for the first time that quiescence can be either driven or suppressed by thermosensory input, and that animal restraint induces quiescence through mechanosensory pathways. Together, these results establish a rich model system for studying how neural and behavioral state transitions are influenced by multiple physiological and environmental conditions. Furthermore, the combination of this spontaneous sleep state with the microfluidic platform serves as a powerful method to uncover the fundamental function of invertebrate sleep using whole-brain imaging, high-throughput behavioral recordings, and longitudinal monitoring across animal lifespan. (abstract adapted from Gonzales, Zhou, & Robinson, 2019).
Magneto-mechanical Neuromodulation
(2015-04-24) Murphy, Daniel B; Robinson, Jacob T; Kemere, Caleb; Hafner, Jason
Noninvasive control of the electrical activity in specific cells in the brain would transform fundamental neuroscience research and the development of therapeutic technologies. Current neural stimulation methods such as electrical or optogenetic stimulation achieve high levels of specificity, but are invasive. Magnetic stimulation is a potentially noninvasive stimulation modality because mammalian tissue is nearly transparent to magnetic fields. In this thesis we investigate a new neural modulation method based on magnetic fields that can potentially achieve similar levels of specificity with much lower invasiveness. Our method will use externally applied, uniform magnetic fields that induce dipole-dipole forces between superparamagnetic iron oxide nanoparticles bound to Piezo1, a mechanically sensitive ion channel. Based on our calculations and early preliminary results, these mechanical forces will be sufficient to open Piezo1, leading to cationic currents, that will alter cell activity. Expression of mutant Piezo1 protein can be targeted to genetically specific populations of cells by means of cell-type specific promoters in transgenic animals. This method is expected to achieve accurate control of genetically specific populations of cells, thereby enabling better research to answer fundamental biological questions and develop novel medical therapies.
Magnetoelectric Materials for Wireless Battery-free Bioelectronics
(2023-04-18) Chen, Joshua C; Robinson, Jacob T
Bioelectronic medicine enables the treatment of a myriad of diseases that are often unresponsive to traditional therapeutics. While existing state-of-the-art devices such as the pacemaker or deep brain stimulator have been used for several decades in the clinic, the core technology has not changed since they were first invented. Major limitations for these technologies is that they have large device footprints which leads to more invasive surgeries, higher risks of site infections, post-operative complications, and the need for repeat surgeries. In this dissertation, I describe the advancement of next generation implantable bioelectronics, moving toward battery-free implants by leveraging a new branch of wireless power transfer technology. These battery-free bioelectronics take advantage of magnetoelectric materials to harvest electrical energy from an applied magnetic field, miniaturizing implants from the centimeter scale down to the millimeter regime. I demonstrate the first digitally programmable, wireless, endovascular peripheral nerve stimulator, called the MagnetoElectric BioImplanT (ME-BIT), which couples CMOS and ME materials. I further miniaturize the neural interface and develop a material based neural stimulator called the Magnetoelectric Nonlinear Metamaterial (MNM) which demonstrates the first nonlinear magnetoelectric coupling coefficient and we take advantage of this engineered metamaterial to directly stimulate excitable cells. Overall, magnetoelectrics hold significant promise for scalable next generation implantable bioelectronics for a variety of different applications.
Role of Anomalous Nanoscale Heat Transfer in gating Magnetogenetic Proteins
(2019-04-18) Polali, Sruthi; Robinson, Jacob T
Genetically encoded ion channels that respond to magnetic fields –‘Magnetogenetics’ — would enable wireless stimulation of specific neurons deep in the brain and thus provide a powerful tool for studying neural correlates of behavior in freely moving animals. A recently engineered magnetogenetic protein consisting of ferritin and TRPV4, dubbed Magneto2.0, was shown to elicit action potentials in neurons when exposed to a magnetic field. The iron-sequestering protein, ferritin serves as the magnetically sensitive domain, while TRPV4 is a cation selective channel that responds to temperature stimuli. However, the mechanism of how the protein senses magnetic field was not understood. Here, we propose a novel mechanism based on the magnetocaloric effect to explain the working of Magneto2.0: A magnetic field reduces the entropy of the ferritin nanoparticles when its magnetic spins align, resulting in an increase in temperature that in turn gates the heat-sensitive TRPV4 channel. This theory is supported by our calculations and experimental data showing that the observed responses are indeed thermally mediated. In exploring this theory, I delve into aspects of nanoscale heat transfer, which deviate significantly from bulk thermal properties. Classical laws predict that there is no significant temperature gradient between a magnetically heated nanoparticle and the surrounding medium and that a single nanoparticle cannot generate enough heat to gate a channel. We measured the temperature and thermal conductance at the vicinity of heated nanoparticles using a novel thermosensor based on silicon microring resonator. A change in temperature shifts the resonant wavelength of the resonator. Temperature near the surface of heated nanoparticles attached directly to these resonators is measured based on the wavelength shift. We show that temperature near surface of the nanoparticles is much higher than that of the surrounding medium and that the thermal conductance at the nanoparticle-water interface is 13 orders of magnitude lower than expected from classical laws. This lowered conductance would enable a single ferritin to gate a nearby TRPV4 channel. In addition to reconciling biological observations with physical properties of magnetic nanoparticles, understanding this mechanism is essential for the design of future magnetogenetic tools with improved magnetic sensitivity.
Scalable nano-electrode electrophysiology in intact small organisms
(2016-10-31) Gonzales, Daniel Luis; Robinson, Jacob T
Electrical measurements from individual cells and synapses in large populations of animals would help reveal fundamental properties of the nervous system and neurological diseases (Bier 2005; Jones, Buckingham, and Sattelle 2005; Kaletta and Hengartner 2006; Lieschke and Currie 2007). Small model organisms like worms and larvae are strong candidates for such large-scale experiments (Yanik, Rohde, and Pardo-Martin 2011); however, current methods to measure electrical activity via patch-clamping methods in these tiny animals requires low-throughput and invasive dissections (Broadie and Bate 1993; Drapeau et al. 1999; Goodman et al. 1998). To overcome these limitations we present nano-SPEARs: nanoscale electrodes that can record electrophysiological activity in small animals without dissections. We designed our prototype device to measure muscle activity in the 1-mm long roundworm Caenorhabditis elegans and show the first extracellular recordings of body-wall muscle activity inside an intact worm. We also reconfigured the geometry of the chip to record from the freshwater cnidarian Hydra littoralis, showing that this platform can be expanded to other animal species. In addition to versatility, our measurement system is scalable, providing a path to high-throughput measurements and offering new screening capabilities for studying human diseases with small model animals. As an example, we establish the first electrophysiological phenotypes for C. elegans models for Amyotrophic Lateral Sclerosis (ALS) and Parkinson’s disease (PD), and show that the PD phenotype can be partially rescued with the drug clioquinol (Tardiff et al. 2012). Together these results demonstrate that nano-SPEARs provide the core technology for scalable electrophysiology microchips that will enable high-throughput, in vivo studies of fundamental neurobiology and neurological diseases. (abstract adapted from Gonzales et al. 2016)
Single-Frame 3D Fluorescence Microscopy with Ultra-Miniature Lensless FlatScope
(2017-06-01) Adams, Jesse K; Robinson, Jacob T; Baraniuk, Richard G; Landes, Christy
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 tradeoff: as lenses become smaller, they must either collect less light or image a smaller field of view. To break this fundamental tradeoff between device size and performance, we present a new concept for 3D fluorescence imaging that replaces lenses with an optimized amplitude mask placed a few hundred microns 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: a lensless microscope that is scarcely larger than an image sensor (roughly 0.2 grams in weight and less than 1 mm thick) and yet able to produce micron-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. 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.
The magnetocaloric model of natural magnetosensation
(2019-04-15) Bell, Andrew; Robinson, Jacob T
Many animals are able to sense the earth’s magnetic field, including varieties of arthropods and members of all major vertebrate groups. The existence of this magnetic sense is widely accepted, and this magnetic control of cellular activity is of great interest in the development of targetable noninvasive neuromodulatory tools as well as from a basic biology perspective. However, the mechanism of action of natural magnetosensation remains unknown, forcing researchers to turn to develop synthetic approaches to stimulate cells using magnetic fields. I discuss how the magnetocaloric effect could explain the puzzling performance of recent synthetic magnetosensors, and outlines a model for natural magnetosensation based on the rotating magnetocaloric effect. These models predicts that heat generated by magnetic nanoparticles may allow proteins to respond to changes in the applied field and allow animals to detect features of the earth's magnetic field. Using these models, I identify the conditions required for the rotating magnetocaloric effect to produce detectable physiological signals in response to the earth's magnetic field, and suggest experiments to distinguish between candidate mechanisms of magnetoreception. Finally, these models also have important implications for the rational design of synthetic magnetically sensitive biological systems. Accordingly I explore the promise and requirements of the development of improved magnetosensory protein complexes and novel bio-compass systems based on principles from the magnetocaloric model of natural magnetosensation.
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Wireless, Battery-Free Bioelectronics in Freely Behaving Rodents for Next-Generation Therapeutics
(2023-12-01) Tuppen, Anne; Robinson, Jacob T
Electrical stimulation therapies have been used to treat numerous disorders and ailments, including Parkinson’s Disease, stroke, and chronic wounds, but much remains unknown about the mechanisms of action and optimal electrical stimulation patterns for affecting positive clinical outcomes. Rodent models are critical for discovering the mechanisms of action of these therapies and developing new stimulation paradigms because they allow the study of animals with precise genetic manipulations used to model a myriad of diseases. Unfortunately, current electrical interfaces compatible with rodent models are typically limited by tethers or batteries for power and data transfer. These tethers and batteries can distract or stress the animal and interfere with locomotion and behavior, making it difficult to study changes in gait, which are critical biomarkers for many conditions. Furthermore, many electrical stimulation therapies require chronic stimulation applied regularly for several weeks, which is difficult to achieve in battery-powered systems that require interruption for charging or replacing batteries. Due to the limitations in scope and duration of experiments using these systems, a wireless battery-free solution is needed. Here, we introduce a platform using magnetoelectric (ME) materials to enable chronic freely behaving rodent experiments. Specifically, we have established robust power delivery using ME materials, developed a behavioral enclosure for chronic experiments, and engineered lightweight, battery-free stimulators for various applications. Our results lay the foundation for a platform enabling chronic freely behaving rodent experiments to facilitate the development of next-generation electrical stimulation therapeutics.

Browsing by Author "Robinson, Jacob T"

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