Nanoparticle-based Plasmonic Transduction for Modulation of Electrically Excitable Cells.
ABSTRACT: There is a compelling need for the development of new sensory and neural prosthetic devices which are capable of more precise point stimulation. Current prosthetic devices suffer from the limitation of low spatial resolution due to the non-specific stimulation characteristics of electrical stimulation, i.e., the spread of electric fields generated. We present a visible light stimulation method for modulating the firing patterns of electrically-excitable cells using surface plasmon resonance phenomena. In in-vitro studies using gold (Au) nanoparticle-coated nanoelectrodes, we show that this method (substrate coated with nanoparticles) has the potential for incorporating this new technology into neural stimulation prosthetics, such as cochlear implants for the deaf, with very high spatial resolution. Au nanoparticles (NPs) were coated on micropipettes using aminosilane linkers; and these micropipettes were used for stimulating and inhibiting the action potential firing patterns of SH-SY5Y human neuroblastoma cells and neonatal cardiomyocytes. Our findings pave the way for development of biomedical implants and neural testing devices using nanoelectrodes capable of temporally and spatially precise excitation and inhibition of electrically-excitable cellular activity.
Project description:Miniaturization of active implantable medical devices is currently compromised by the available means for electrically powering them. Most common energy supply techniques for implants--batteries and inductive couplers--comprise bulky parts which, in most cases, are significantly larger than the circuitry they feed. Here, for overcoming such miniaturization bottleneck in the case of implants for electrical stimulation, it is proposed to make those implants act as rectifiers of high frequency bursts supplied by remote electrodes. In this way, low frequency currents will be generated locally around the implant and these low frequency currents will perform stimulation of excitable tissues whereas the high frequency currents will cause only innocuous heating. The present study numerically demonstrates that low frequency currents capable of stimulation can be produced by a miniature device behaving as a diode when high frequency currents, neither capable of thermal damage nor of stimulation, flow through the tissue where the device is implanted. Moreover, experimental evidence is provided by an in vivo proof of concept model consisting of an anesthetized earthworm in which a commercial diode was implanted. With currently available microelectronic techniques, very thin stimulation capsules (diameter <500 µm) deliverable by injection are easily conceivable.
Project description:Brain function can be best studied by simultaneous measurements and modulation of the multifaceted signaling at the cellular scale. Extensive efforts have been made to develop multifunctional neural probes, typically involving highly specialized fabrication processes. Here, we report a novel multifunctional neural probe platform realized by applying ultrathin nanoelectronic coating (NEC) on the surfaces of conventional microscale devices such as optical fibers and micropipettes. We fabricated the NECs by planar photolithography techniques using a substrate-less and multilayer design, which host arrays of individually addressed electrodes with an overall thickness below 1 ?m. Guided by an analytic model and taking advantage of the surface tension, we precisely aligned and coated the NEC devices on the surfaces of these conventional microprobes and enabled electrical recording capabilities on par with the state-of-the-art neural electrodes. We further demonstrated optogenetic stimulation and controlled drug infusion with simultaneous, spatially resolved neural recording in a rodent model. This study provides a low-cost, versatile approach to construct multifunctional neural probes that can be applied to both fundamental and translational neuroscience.
Project description:The ability to electrically stimulate neural and other excitable tissues in behaving experimental animals is invaluable for both the development of neural prostheses and basic neurological research. We developed a fully implantable neural stimulator that is able to deliver two channels of intra-cochlear electrical stimulation in the rat. It is powered via a novel omni-directional inductive link and includes an on-board microcontroller with integrated radio link, programmable current sources and switching circuitry to generate charge-balanced biphasic stimulation. We tested the implant in vivo and were able to elicit both neural and behavioural responses. The implants continued to function for up to five months in vivo. While targeted to cochlear stimulation, with appropriate electrode arrays the stimulator is well suited to stimulating other neurons within the peripheral or central nervous systems. Moreover, it includes significant on-board data acquisition and processing capabilities, which could potentially make it a useful platform for telemetry applications, where there is a need to chronically monitor physiological variables in unrestrained animals.
Project description:The advancement of neural prostheses requires implantable neural electrodes capable of electrically stimulating or recording signals from neurons chronically. Unfortunately, the implantation injury and presence of foreign bodies lead to chronic inflammation, resulting in neuronal death in the vicinity of electrodes. A key mediator of inflammation and neuronal loss are reactive oxygen and nitrogen species (RONS). To mitigate the effect of RONS, a superoxide dismutase mimic compound, manganese(III) meso-tetrakis-(N-(2-aminoethyl)pyridinium-2-yl) porphyrin (iSODm), was synthesized to covalently attach to the neural probe surfaces. This new compound showed high catalytic superoxide scavenging activity. In microglia cell line cultures, the iSODm coating effectively reduced superoxide production and altered expression of iNOS, NADPH oxidase, and arginase. After 1?week of implantation, iSODm coated electrodes showed significantly lower expression of markers for oxidative stress immediately adjacent to the electrode surface, as well as significantly less neurons undergoing apoptosis. STATEMENT OF SIGNIFICANCE: One critical challenge in the translation of neural electrode technology to clinically viable devices for brain computer interface or deep brain stimulation applications is the chronic degradation of the device performance due to neuronal degeneration around the implants. One of the key mediators of inflammation and neuronal degeneration is reactive oxygen and nitrogen species released by injured neurons and inflammatory microglia. This research takes a biomimetic approach to synthesize a compound having similar reactivity as superoxide dismutase, which can catalytically scavenge reactive oxygen and nitrogen species, thereby reducing oxidative stress and decreasing neuronal degeneration. By immobilizing the compound covalently on the surface of neural implants, we show that the neuronal degeneration and oxidative stress around the implants is significantly reduced.
Project description:Intracellular recording of action potentials is important to understand electrically-excitable cells. Recently, vertical nanoelectrodes have been developed to achieve highly sensitive, minimally invasive and large-scale intracellular recording. It has been demonstrated that the vertical geometry is crucial for the enhanced signal detection. Here we develop nanoelectrodes of a new geometry, namely nanotubes of iridium oxide. When cardiomyocytes are cultured upon those nanotubes, the cell membrane not only wraps around the vertical tubes but also protrudes deep into the hollow centre. We show that this nanotube geometry enhances cell-electrode coupling and results in larger signals than solid nanoelectrodes. The nanotube electrodes also afford much longer intracellular access and are minimally invasive, making it possible to achieve stable recording up to an hour in a single session and more than 8 days of consecutive daily recording. This study suggests that the nanoelectrode performance can be significantly improved by optimizing the electrode geometry.
Project description:Contemporary auditory prostheses ("cochlear implants") employ arrays of stimulating electrodes implanted in the scala tympani of the cochlea. Such arrays have been implanted in some 100,000 profoundly or severely deaf people worldwide and arguably are the most successful of present-day neural prostheses. Nevertheless, most implant users show poor understanding of speech in noisy backgrounds, poor pitch recognition, and poor spatial hearing, even when using bilateral implants. Many of these limitations can be attributed to the remote location of stimulating electrodes relative to excitable cochlear neural elements. That is, a scala tympani electrode array lies within a bony compartment filled with electrically conductive fluid. Moreover, scala tympani arrays typically do not extend to the apical turn of the cochlea in which low frequencies are represented. In the present study, we have tested in an animal model an alternative to the conventional cochlear implant: a multielectrode array implanted directly into the auditory nerve. We monitored the specificity of stimulation of the auditory pathway by recording extracellular unit activity at 32 sites along the tonotopic axis of the inferior colliculus. The results demonstrate the activation of specific auditory nerve populations throughout essentially the entire frequency range that is represented by characteristic frequencies in the inferior colliculus. Compared to conventional scala tympani stimulation, thresholds for neural excitation are as much as 50-fold lower and interference between electrodes stimulated simultaneously is markedly reduced. The results suggest that if an intraneural stimulating array were incorporated into an auditory prosthesis system for humans, it could offer substantial improvement in hearing replacement compared to contemporary cochlear implants.
Project description:Interaural time difference (ITD) arises whenever a sound outside of the median plane arrives at the two ears. There is evidence that ITD in the rapidly varying fine structure of a sound is most important for sound localization and for understanding speech in noise. Cochlear implants (CIs), neural prosthetic devices that restore hearing in the profoundly deaf, are increasingly implanted to both ears to provide implantees with the advantages of binaural hearing. CI listeners have been shown to be sensitive to fine structure ITD at low pulse rates, but their sensitivity declines at higher pulse rates that are required for speech coding. We hypothesize that this limitation in electric stimulation is at least partially due to binaural adaptation associated with periodic stimulation. Here, we show that introducing binaurally synchronized jitter in the stimulation timing causes large improvements in ITD sensitivity at higher pulse rates. Our experimental results demonstrate that a purely temporal trigger can cause recovery from binaural adaptation. Thus, binaurally jittered stimulation may improve several aspects of binaural hearing in bilateral recipients of neural auditory prostheses.
Project description:Neural activity modulates the maturation of synapses and their organization into functional circuits by regulating activity-dependent signaling pathways. Phosphorylation of cyclic AMP/Ca(2+)-responsive element-binding protein (CREB) is widely accepted as a stimulus-inducible event driven by calcium influx into depolarized neurons. In turn, phosphorylated CREB (pCREB) activates the transcription of brain-derived neurotrophic factor (BDNF), which is needed for synaptic transmission and long-term potentiation. We examined how these molecular events are influenced by sensorineural hearing loss and long-term reactivation via cochlear implants. Sensorineural hearing loss reduced the expression of pCREB and BDNF. In contrast, deafened animals subject to long-term, unilateral intracochlear electrical stimulation exhibited an increased expression of pCREB and BDNF in the contralateral auditory cortical neurons, relative to ipsilateral ones. These changes induced by cochlear implants are further accompanied by the activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which has been implicated in long-lasting forms of synaptic plasticity. Because CREB and BDNF are critical modulators of synaptic plasticity, our data describe for the first time possible molecular candidate genes, which are altered in the auditory cortex, following cochlear implantation. These findings provide insights into adaptive, molecular mechanisms recruited by the brain upon functional electrical stimulation by neural prosthetic devices.
Project description:In all commercial cochlear implant (CI) devices, the electric stimulation is performed with a rectangular pulse that generally has two phases of opposite polarity. To date, developing new stimulation strategies has relied on the efficacy of this shape. Here, we investigate the potential of a novel stimulation paradigm that uses biophysically-inspired electrical ramped pulses. Using electrically-evoked auditory brainstem response (eABR) recordings in mice, we found that less charge, but higher current level amplitude, is needed to evoke responses with ramped shapes that are similar in amplitude to responses obtained with rectangular shapes. The most charge-efficient pulse shape had a rising ramp over both phases, supporting findings from previous in vitro studies. This was also true for longer phase durations. Our study presents the first physiological data on CI-stimulation with ramped pulse shapes. By reducing charge consumption ramped pulses have the potential to produce more battery-efficient CIs and may open new perspectives for designing other efficient neural implants in the future.
Project description:Interfacing organic electronics with biological substrates offers new possibilities for biotechnology due to the beneficial properties exhibited by organic conducting polymers. These polymers have been used for cellular interfaces in several fashions, including cellular scaffolds, neural probes, biosensors and actuators for drug release. Recently, an organic photovoltaic blend has been exploited for neuronal stimulation via a photo-excitation process. Here, we document the use of a single-component organic film of poly(3-hexylthiophene) (P3HT) to trigger neuronal firing upon illumination. Moreover, we demonstrate that this bio-organic interface restored light sensitivity in explants of rat retinas with light-induced photoreceptor degeneration. These findings suggest that all-organic devices may play an important future role in sub-retinal prosthetic implants.