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GHz Ultrasonic Chip-Scale Device Induces Ion Channel Stimulation in Human Neural Cells.

ABSTRACT: Emergent trends in the device development for neural prosthetics have focused on establishing stimulus localization, improving longevity through immune compatibility, reducing energy re-quirements, and embedding active control in the devices. Ultrasound stimulation can single-handedly address several of these challenges. Ultrasonic stimulus of neurons has been studied extensively from 100?kHz to 10?MHz, with high penetration but less localization. In this paper, a chip-scale device consisting of piezoelectric Aluminum Nitride ultrasonic transducers was engineered to deliver gigahertz (GHz) ultrasonic stimulus to the human neural cells. These devices provide a path towards complementary metal oxide semiconductor (CMOS) integration towards fully controllable neural devices. At GHz frequencies, ultrasonic wavelengths in water are a few microns and have an absorption depth of 10-20?µm. This confinement of energy can be used to control stimulation volume within a single neuron. This paper is the first proof-of-concept study to demonstrate that GHz ultrasound can stimulate neurons in vitro. By utilizing optical calcium imaging, which records calcium ion flux indicating occurrence of an action potential, this paper demonstrates that an application of a nontoxic dosage of GHz ultrasonic waves [Formula: see text] caused an average normalized fluorescence intensity recordings >1.40 for the calcium transients. Electrical effects due to chip-scale ultrasound delivery was discounted as the sole mechanism in stimulation, with effects tested at ??=?0.01 statistical significance amongst all intensities and con-trol groups. Ionic transients recorded optically were confirmed to be mediated by ion channels and experimental data suggests an insignificant thermal contributions to stimulation, with a predicted increase of 0.03 oC for [Formula: see text] This paper paves the experimental framework to further explore chip-scale axon and neuron specific neural stimulation, with future applications in neural prosthetics, chip scale neural engineering, and extensions to different tissue and cell types.

SUBMITTER: Balasubramanian PS

PROVIDER: S-EPMC7033194 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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GHz Ultrasonic Chip-Scale Device Induces Ion Channel Stimulation in Human Neural Cells.

Balasubramanian Priya S PS Singh Ankur A Singh Ankur A Xu Chris C Lal Amit A

Scientific reports 20200220 1

Emergent trends in the device development for neural prosthetics have focused on establishing stimulus localization, improving longevity through immune compatibility, reducing energy re-quirements, and embedding active control in the devices. Ultrasound stimulation can single-handedly address several of these challenges. Ultrasonic stimulus of neurons has been studied extensively from 100 kHz to 10 MHz, with high penetration but less localization. In this paper, a chip-scale device consisting of ...[more]

PMID: 32080204

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Project description:Functional imaging has been a widely established method for the assessment of ion channel function in vitro. Conventional infrastructure used for in vitro functional analysis of ion channels is typically proprietary, non-customizable, expensive, and requires a high level of skill to use and maintain. 3D desktop printing, which is employed in the rapid prototyping field, allows for quick engineering of alternatives to conventional imaging infrastructure that are customizable, low cost, and user friendly. Here, we describe an ultra-low-cost microfluidic lab-on-a-chip (LOC) device manufactured using acrylonitrile butadiene styrene (ABS) for in vitro functional imaging of ion channels that can quickly and easily be reconstructed using three-dimensional (3D) desktop printing. The device is light weight (<5 g), small (20 mm × 49 mm), and extremely low cost (<EUR 1). We simulate fluidics within the printed channels and assess the suitability of the engineered chamber to generate homogeneous mixtures during solution exchange. We demonstrate the usability of the 3D printed microfluidic device in a case study using Fluo-4-loaded human embryonal kidney-derived (HEK293) cells, recombinantly expressing the capsaicin receptor, transient receptor potential vanilloid receptor type 1 (TRPV1), as a model system. In the case study, we confirm its applicability to solution exchange for chemical stimulation and parallel functional time-lapse fluorescence microscopy-based calcium imaging. We assess the suitability of ABS for culturing HEK293 cells inside the microfluidic LOC, based on qualitative analysis of microscopic transmission light images of ABS-exposed HEK293 cells and confirm the previously reported biocompatibility of ABS. To highlight the versatility of the 3D printed microfluidic device, we provide an example for multiplication of the shown concept within a 3D printed multichannel microfluidic LOC to be used, for example, in a higher throughput format for parallelized functional analysis of ion channels. While this work focusses on Ca2+ imaging with TRPV1 channels, the device may also be useful for application with other ion channel types and in vitro models.

Project description:Neural stimulation is an important method used to activate or inhibit action potentials of the neuronal anatomical targets found in the brain, central nerve and peripheral nerve. The neural stimulator system produces biphasic pulses that deliver balanced charge into tissue from single or multichannel electrodes. The timing and amplitude of these biphasic pulses are precisely controlled by the neural stimulator software or imbedded algorithms. Amplitude mismatch between the anodic current and cathodic current of the biphasic pulse will cause permanently damage for the neural tissues. The main goal of our circuit and layout design is to implement a 16-channel biphasic current mode programmable neural stimulator with calibration to minimize the current mismatch caused by inherent complementary metal oxide semiconductor (CMOS) manufacturing processes.This paper presents a 16-channel constant current mode neural stimulator chip. Each channel consists of a 7-bit controllable current DAC used as sink and source current driver. To reduce the LSB quantization error and the current mismatch, an automatic calibration circuit and flow diagram is presented in this paper. There are two modes of operation of the stimulator chip-namely, stimulation mode and calibration mode. The chip also includes a digital interface used to control the stimulator parameters and calibration levels specific for each individual channel.This stimulator Application Specific Integrated Circuit (ASIC) is designed and fabricated in a 0.18 μm High-Voltage CMOS technology that allows for ±20 V power supply. The full-scale stimulation current was designed to be at 1 mA per channel. The output current was shown to be constant throughout the timing cycles over a wide range of electrode load impedances. The calibration circuit was also designed to reduce the effect of CMOS process variation of the P-channel metal oxide semiconductor (PMOS) and N-channel metal oxide semiconductor (NMOS) devices that will result in charge delivery to have less than 0.13% error.A 16-channel integrated biphasic neural stimulator chip with calibration is presented in this paper. The stimulator circuit design was simulated and the chip layout was completed. The chip layout was verified using design rules check (DRC) and layout versus schematic (LVS) design check using computer aided design (CAD) software. The test results we presented show constant current stimulation with charge balance error within 0.13% least-significant-bit (LSB). This LSB error was consistent throughout a variety stimulation patterns and electrode load impedances.

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GHz Ultrasonic Chip-Scale Device Induces Ion Channel Stimulation in Human Neural Cells.

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GHz Ultrasonic Chip-Scale Device Induces Ion Channel Stimulation in Human Neural Cells.

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