Feasibility Study for a High-Frequency Flexible Ultrasonic Cuff for High-Precision Vagus Nerve Ultrasound Neuromodulation.

In the emerging research field of bioelectronic medicine, it has been indicated that neuromodulation of the Vagus Nerve (VN) has the potential to treat various conditions such as epilepsy, depression, and autoimmune diseases. In order to reduce side effects, as well as to increase the effectiveness of the delivered therapy, sub-fascicle stimulation specificity is required. In the electrical domain, increasing spatial selectivity can only be achieved using invasive and potentially damaging approaches like compressive forces or nerve penetration. To avoid these invasive methods while obtaining a high spatial selectivity, a 2 mm diameter extraneural cuff-shaped proof-of-concept design with integrated Lead Zirconate Titanate (PZT) based ultrasound (US) transducers is proposed in this paper. For the development of the proposed concept, wafer-level microfabrication techniques are employed. Moreover, acoustic measurements are performed on the device, in order to characterize the ultrasonic beam profiles of the integrated PZT-based US transducers. A focal spot size of around 200 µm by 200 µm is measured for the proposed cuff. Moreover, the curvature of the device leads to constructive interference of the US waves originating from multiple PZT-based US transducers, which in turn leads to an increase of 45% in focal pressure compared to the focal pressure of a single PZT-based US transducer. Integrating PZT-based US transducers in an extraneural cuff-shaped design has the potential to achieve high-precision US neuromodulation of the Vagus Nerve without requiring intraneural implantation.

Surface modification of multilayer graphene electrodes by local printing of platinum nanoparticles using spark ablation for neural interfacing.

In this paper, we present the surface modification of multilayer graphene electrodes with platinum (Pt) nanoparticles (NPs) using spark ablation. This method yields an individually selective local printing of NPs on an electrode surface at room temperature in a dry process. NP printing is performed as a post-process step to enhance the electrochemical characteristics of graphene electrodes. The NP-printed electrode shows significant improvements in impedance, charge storage capacity (CSC), and charge injection capacity (CIC), versus the equivalent electrodes without NPs. Specifically, electrodes with 40% NP surface density demonstrate 4.5 times lower impedance, 15 times higher CSC, and 4 times better CIC. Electrochemical stability, assessed via continuous cyclic voltammetry (CV) and voltage transient (VT) tests, indicated minimal deviations from the initial performance, while mechanical stability, assessed via ultrasonic vibration, is also improved after the NP printing. Importantly, NP surface densities up to 40% maintain the electrode optical transparency required for compatibility with optical imaging and optogenetics. These results demonstrate selective NP deposition and local modification of electrochemical properties in graphene electrodes for the first time, enabling the cohabitation of graphene electrodes with different electrochemical and optical characteristics on the same substrate for neural interfacing.

Non-monolithic fabrication of thin-film microelectrode arrays on PMUT transducers as a bimodal neuroscientific investigation tool.

Ultrasound (US)-based neuromodulation has recently emerged as a spatially selective yet non-invasive alternative to conventional electrically-based neural interfaces. However, the fundamental mechanisms of US neuromodulation are not yet clarified. Thus, there is a need for in-vitro bimodal investigation tools that allow us to compare the effect of US versus electrically-induced neural activity in the vicinity of the transducing element. To this end, we propose a MicroElectrode-MicroTransducer Array (MEMTA), where a dense array of electrodes is co-fabricated on top of a similarly dense array of US transducers.In this paper, we test the proof of concept for such co-fabrication using a non-monolithic approach, where, at its most challenging scenario, desired topologies require electrodes to be formed directly on top of fragile piezoelectric micromachined ultrasound transducer (PMUTs) membranes. On top of the PMUTs, a thin-film microelectrode array was developed utilizing microfabrication processes, including metal sputtering, lithography, etching and soft encapsulation. The samples were analysed through focused ion beam-scanning electron microscopy (FIB-SEM), and the results have shown that damage to the membranes does not occur during any of the process steps. This paper proves that the non-monolithic development of a miniaturised bimodal neuroscientific investigation tool can be achieved, thus, opening up a series of possibilities for further understanding and investigation of the nervous system.

On the Stimulation Artifact Reduction during Electrophysiological Recording of Compound Nerve Action Potentials.

Recording neuronal activity triggered by electrical impulses is a powerful tool in neuroscience research and neural engineering. It is often applied in acute electrophysiological experimental settings to record compound nerve action potentials. However, the elicited neural response is often distorted by electrical stimulus artifacts, complicating subsequent analysis. In this work, we present a model to better understand the effect of the selected amplifier configuration and the location of the ground electrode in a practical electrophysiological nerve setup. Simulation results show that the stimulus artifact can be reduced by more than an order of magnitude if the placement of the ground electrode, its impedance, and the amplifier configuration are optimized. We experimentally demonstrate the effects in three different settings, in-vivo and in-vitro.

Energy Savings of Multi-Channel Neurostimulators with Non-Rectangular Current-Mode Stimuli Using Multiple Supply Rails.

In neuromodulation applications, conventional current mode stimulation is often preferred over its voltage mode equivalent due to its good control of the injected charge. However, it comes at the cost of less energy-efficient output stages. To increase energy efficiency, recent studies have explored non-rectangular stimuli. The current work highlights the importance of an adaptive supply for an output stage with programmable non-rectangular stimuli and accordingly proposes a system-level architecture for multi-channel stimulators. In the proposed architecture, a multi-output DC/DC Converter (DDC) allows each channel to choose among the available supply levels (i.e., DDC outputs) independently and based on its instant voltage/current requirement. A system-level analysis is carried out in Matlab to calculate the possible energy savings of this solution, compared to the conventional approach with a fixed supply. The energy savings have been simulated for a variety of supply levels and waveform amplitudes, suggesting energy savings of up to 83% when employing 6 DDC outputs and the lowest current amplitude explored ( 250 µA), and as high as 26% for a full-scale amplitude (4 mA).

Multilayer CVD graphene electrodes using a transfer-free process for the next generation of optically transparent and MRI-compatible neural interfaces.

Multimodal platforms combining electrical neural recording and stimulation, optogenetics, optical imaging, and magnetic resonance (MRI) imaging are emerging as a promising platform to enhance the depth of characterization in neuroscientific research. Electrically conductive, optically transparent, and MRI-compatible electrodes can optimally combine all modalities. Graphene as a suitable electrode candidate material can be grown via chemical vapor deposition (CVD) processes and sandwiched between transparent biocompatible polymers. However, due to the high graphene growth temperature (≥ 900 °C) and the presence of polymers, fabrication is commonly based on a manual transfer process of pre-grown graphene sheets, which causes reliability issues. In this paper, we present CVD-based multilayer graphene electrodes fabricated using a wafer-scale transfer-free process for use in optically transparent and MRI-compatible neural interfaces. Our fabricated electrodes feature very low impedances which are comparable to those of noble metal electrodes of the same size and geometry. They also exhibit the highest charge storage capacity (CSC) reported to date among all previously fabricated CVD graphene electrodes. Our graphene electrodes did not reveal any photo-induced artifact during 10-Hz light pulse illumination. Additionally, we show here, for the first time, that CVD graphene electrodes do not cause any image artifact in a 3T MRI scanner. These results demonstrate that multilayer graphene electrodes are excellent candidates for the next generation of neural interfaces and can substitute the standard conventional metal electrodes. Our fabricated graphene electrodes enable multimodal neural recording, electrical and optogenetic stimulation, while allowing for optical imaging, as well as, artifact-free MRI studies.

Thin Film Encapsulation for LCP-Based Flexible Bioelectronic Implants: Comparison of Different Coating Materials Using Test Methodologies for Life-Time Estimation.

Liquid crystal polymer (LCP) has gained wide interest in the electronics industry largely due to its flexibility, stable insulation and dielectric properties and chip integration capabilities. Recently, LCP has also been investigated as a biocompatible substrate for the fabrication of multielectrode arrays. Realizing a fully implantable LCP-based bioelectronic device, however, still necessitates a low form factor packaging solution to protect the electronics in the body. In this work, we investigate two promising encapsulation coatings based on thin-film technology as the main packaging for LCP-based electronics. Specifically, a HfO2-based nanolaminate ceramic (TFE1) deposited via atomic layer deposition (ALD), and a hybrid Parylene C-ALD multilayer stack (TFE2), both with a silicone finish, were investigated and compared to a reference LCP coating. T-peel, water-vapour transmission rate (WVTR) and long-term electrochemical impedance spectrometry (EIS) tests were performed to evaluate adhesion, barrier properties and overall encapsulation performance of the coatings. Both TFE materials showed stable impedance characteristics while submerged in 60 °C saline, with TFE1-silicone lasting more than 16 months under a continuous 14V DC bias (experiment is ongoing). The results presented in this work show that WVTR is not the main factor in determining lifetime, but the adhesion of the coating to the substrate materials plays a key role in maintaining a stable interface and thus longer lifetimes.

Focused ultrasound neuromodulation on a multiwell MEA.

BACKGROUND: Microelectrode arrays (MEA) enable the measurement and stimulation of the electrical activity of cultured cells. The integration of other neuromodulation methods will significantly enhance the application range of MEAs to study their effects on neurons. A neuromodulation method that is recently gaining more attention is focused ultrasound neuromodulation (FUS), which has the potential to treat neurological disorders reversibly and precisely. METHODS: In this work, we present the integration of a focused ultrasound delivery system with a multiwell MEA plate. RESULTS: The ultrasound delivery system was characterised by ultrasound pressure measurements, and the integration with the MEA plate was modelled with finite-element simulations of acoustic field parameters. The results of the simulations were validated with experimental visualisation of the ultrasound field with Schlieren imaging. In addition, the system was tested on a murine primary hippocampal neuron culture, showing that ultrasound can influence the activity of the neurons. CONCLUSIONS: Our system was demonstrated to be suitable for studying the effect of focused ultrasound on neuronal cultures. The system allows reproducible experiments across the wells due to its robustness and simplicity of operation.

PDMS-Parylene Adhesion Improvement via Ceramic Interlayers to Strengthen the Encapsulation of Active Neural Implants.

Parylene-C has been used as a substrate and encapsulation material for many implantable medical devices. However, to ensure the flexibility required in some applications, minimize tissue reaction, and protect parylene from degradation in vivo an additional outmost layer of polydimethylsiloxane (PDMS) is desired. In such a scenario, the adhesion of PDMS to parylene is of critical importance to prevent early failure caused by delamination in the harsh environment of the human body. Towards this goal, we propose a method based on creating chemical covalent bonds using intermediate ceramic layers as adhesion promoters between PDMS and parylene.To evaluate our concept, we prepared three different sets of samples with PDMS on parylene without and with oxygen plasma treatment (the most commonly employed method to increase adhesion), and samples with our proposed ceramic intermediate layers of silicon carbide (SiC) and silicon dioxide (SiO2). The samples were soaked in phosphate-buffered saline (PBS) solution at room temperature and were inspected under an optical microscope. To investigate the adhesion property, cross-cut tape tests and peel tests were performed. The results showed a significant improvement of the adhesion and in-soak long-term performance of our proposed encapsulation stack compared with PDMS on parylene and PDMS on plasma-treated parylene. We aim to use the proposed solution to package bare silicon chips on active implants.

Towards CMOS Bulk Sensing for In-Situ Evaluation of ALD Coatings for Millimeter Sized Implants.

To meet the dimensional requirements for bioelectronic medicine, new packaging solutions are needed that could enable small, light-weight and flexible implants. For protecting the implantable electronics against biofluids, recently various atomic layer deposited (ALD) coatings have been proposed with high barrier properties. Before implantation, however, the protective coating should be evaluated for any defects which could otherwise lead to leakage and device failure. In these cases, the conventional helium leak test method can no longer be used due to the millimeter size of the implant. Therefore, an in-situ sensing platform is needed that could evaluate the coating and justify the implantation of the final device. In this work, we explore the possibility of using the CMOS bulk for such a platform. Towards this aim, as a proof of concept, test chips were made in a standard 6-metal 0.18 µm CMOS process and for the connection to the bulk, a p+ diffusion was used. A group of samples was then coated with an ALD multilayer. For coating evaluation, off-chip DC current leakage and impedance measurements were carried out in saline between the CMOS bulk and a platinum reference electrode. Results were compared between non-coated and coated chips that clearly demonstrated the potential of using the bulk as a sensing platform for coating evaluations. This novel approach could pave the way towards an all integrated in-situ hermeticity test, currently missing in mm-size implants.

A Chip Integrity Monitor for Evaluating Moisture/Ion Ingress in mm-Sized Single-Chip Implants.

For mm-sized implants incorporating silicon integrated circuits, ensuring lifetime operation of the chip within the corrosive environment of the body still remains a critical challenge. For the chip's packaging, various polymeric and thin ceramic coatings have been reported, demonstrating high biocompatibility and barrier properties. Yet, for the evaluation of the packaging and lifetime prediction, the conventional helium leak test method can no longer be applied due to the mm-size of such implants. Alternatively, accelerated soak studies are typically used instead. For such studies, early detection of moisture/ion ingress using an in-situ platform may result in a better prediction of lifetime functionality. In this work, we have developed such a platform on a CMOS chip. Ingress of moisture/ions would result in changes in the resistance of the interlayer dielectrics (ILD) used within the chip and can be tracked using the proposed system, which consists of a sensing array and an on-chip measurement engine. The measurement system uses a novel charge/discharge based time-mode resistance sensor that can be implemented using simple yet highly robust circuitry. The sensor array is implemented together with the measurement engine in a standard 0.18  µm 6-metal CMOS process. The platform was validated through a series of dry and wet measurements. The system can measure the ILD resistance with values of up to 0.504 peta-ohms, with controllable measurement steps that can be as low as 0.8 M Ω. The system works with a supply voltage of 1.8 V, and consumes 4.78 mA. Wet measurements in saline demonstrated the sensitivity of the platform in detecting moisture/ion ingress. Such a platform could be used both in accelerated soak studies and during the implant's life-time for monitoring the integrity of the chip's packaging.

An Ultra High-Frequency 8-Channel Neurostimulator Circuit With [Formula: see text] Peak Power Efficiency.

In order to recruit neurons in excitable tissue, constant current neural stimulators are commonly used. Recently, ultra high-frequency (UHF) stimulation has been proposed and proven to have the same efficacy as constant-current stimulation. UHF stimulation uses a fundamentally different way of activating the tissue: each stimulation phase is made of a burst of current pulses with adjustable amplitude injected into the tissue at a high (e.g., [Formula: see text]) frequency. This paper presents the design, integrated circuit (IC) implementation, and measurement results of a power efficient multichannel UHF neural stimulator. The core of the neurostimulator is based on our previously proposed architecture of an inductor-based buck-boost dc-dc converter without the external output capacitor. The ultimate goal of this work is to increase the power efficiency of the UHF stimulator for multiple-channel operation, while keeping the number of external components minimal. To this end, a number of novel approaches were employed in the integrated circuit design domain. More specifically, a novel zero-current detection scheme is proposed. It allows to remove the freewheel diode typically used in dc-dc converters to prevent current to flow back from the load to the inductor. Furthermore, a gate-driver circuit is implemented which allows the use of thin gate-oxide transistors as high-voltage switches. By doing so, and exploiting the fundamental working principle of the proposed current-controlled UHF stimulator, the need for a high-voltage supply is eliminated and the stimulator is powered up from a [Formula: see text] input voltage. Both the current detection technique and the gate driving circuit of the current implementation allow to boost the power efficiency up to [Formula: see text] when compared to previous UHF stimulator works. A peak power efficiency of [Formula: see text] is achieved, while 8 independent channels with 16 fully configurable electrodes are used. The circuit is implemented in a [Formula: see text] HV process, and the total chip area is [Formula: see text].

Comments on "Compact, Energy-Efficient High-Frequency Switched Capacitor Neural Stimulator With Active Charge Balancing".

This manuscript points out some mistakes in the Introduction and in the table of comparison of a paper already published in this journal by Hsu and Schmid [1]. Although the main claim of [1] is still preserved, we believe the paper needs to be rectified for scientific correctness of the work.

Effect of Signals on the Encapsulation Performance of Parylene Coated Platinum Tracks for Active Medical Implants.

Platinum is widely used as the electrode material for implantable devices. Owing to its high biostability and corrosion resistivity, platinum could also be used as the main metallization for tracks in active implants. Towards this goal, in this work we investigate the stability of parylene-coated Pt tracks using passive and active tests. The test samples in this study are Pt-on-SiO2 interdigitated comb structures. During testing all samples were immersed in saline for 150 days; for passive testing, the samples were left unbiased, whilst for active testing, samples were exposed to two different stress signals: a 5 V DC and a 5 Vp 500 pulses per second biphasic signal. All samples were monitored over time using impedance spectroscopy combined with optical inspection. After the first two weeks of immersion, delamination spots were observed on the Pt tracks for both passive and actively tested samples. Despite the delamination spots, the unbiased samples maintained high impedances until the end of the study. For the actively stressed samples, two different failure mechanisms were observed which were signal related. DC stressed samples showed severe parylene cracking mainly due to the electrolysis of the condensed water. Biphasically stressed samples showed gradual Pt dissolution and migration. These results contribute to a better understanding of the failure mechanisms of Pt tracks in active implants and suggest that new testing paradigms may be necessary to fully assess the long-term reliability of these devices.

An Energy-Efficient, Inexpensive, Spinal Cord Stimulator with Adaptive Voltage Compliance for Freely Moving Rats.

This paper presents the design and fabrication of an implantable control unit intended for epidural spinal cord stimulation (ESCS) in rats. The device offers full programmability over stimulation parameters and delivers a constant current to an electrode array to be located within the spinal canal. It implements an adaptive voltage compliance in order to reduce the unnecessary power dissipation often experienced in current-controlled stimulation (CCS) devices. The compliance is provided by an adjustable boost converter that offers a voltage output in the range of 6.24 V to 28 V, allowing the device to deliver currents up to 1 mA through loads up to $25 \mathrm {k}\Omega $. The system has been fabricated using discrete components, paving the way to an inexpensive product that can easily be manufactured and batch produced. The control unit occupies a total volume of ~13.5 cm3 and therefore fulfills the size restrictions of a system to be implanted in a rat. Results indicate that by adjusting the voltage compliance a total power efficiency up to 35.5% can be achieved, saving around 60 mW when using lower stimulation currents or operating on smaller impedances. The achieved efficiency is the highest compared to similar stateof-the-art systems.

Realizing flexible bioelectronic medicines for accessing the peripheral nerves - technology considerations.

Patients suffering from conditions such as paralysis, diabetes or rheumatoid arthritis could in the future be treated in a personalised manner using bioelectronic medicines (BEms) (Nat Rev Drug Discov 13:399-400, 2013, Proc Natl Acad Sci USA 113:8284-9, 2016, J Intern Med 282:37-45, 2017). To deliver this personalised therapy based on electricity, BEms need to target various sites in the human body and operate in a closed-loop manner. The specific conditions and anatomy of the targeted sites pose unique challenges in the development of BEms. With a focus on BEms based on flexible substrates for accessing small peripheral nerves, this paper discusses several system-level technology considerations related to the development of such devices. The focus is mainly on miniaturisation and long-term operation. We present an overview of common substrate and electrode materials, related processing methods, and discuss assembly, miniaturisation and long-term stability issues.

Towards a wearable near infrared spectroscopic probe for monitoring concentrations of multiple chromophores in biological tissue in vivo.

The first wearable multi-wavelength technology for functional near-infrared spectroscopy has been developed, based on a custom-built 8-wavelength light emitting diode (LED) source. A lightweight fibreless probe is designed to monitor changes in the concentrations of multiple absorbers (chromophores) in biological tissue, the most dominant of which at near-infrared wavelengths are oxyhemoglobin and deoxyhemoglobin. The use of multiple wavelengths enables signals due to the less dominant chromophores to be more easily distinguished from those due to hemoglobin and thus provides more complete and accurate information about tissue oxygenation, hemodynamics, and metabolism. The spectroscopic probe employs four photodiode detectors coupled to a four-channel charge-to-digital converter which includes a charge integration amplifier and an analogue-to-digital converter (ADC). Use of two parallel charge integrators per detector enables one to accumulate charge while the other is being read out by the ADC, thus facilitating continuous operation without dead time. The detector system has a dynamic range of about 80 dB. The customized source consists of eight LED dies attached to a 2 mm × 2 mm substrate and encapsulated in UV-cured epoxy resin. Switching between dies is performed every 20 ms, synchronized to the detector integration period to within 100 ns. The spectroscopic probe has been designed to be fully compatible with simultaneous electroencephalography measurements. Results are presented from measurements on a phantom and a functional brain activation study on an adult volunteer, and the performance of the spectroscopic probe is shown to be very similar to that of a benchtop broadband spectroscopy system. The multi-wavelength capabilities and portability of this spectroscopic probe will create significant opportunities for in vivo studies in a range of clinical and life science applications.

Flexible active electrode arrays with ASICs that fit inside the rat's spinal canal.

Epidural spinal cord electrical stimulation (ESCS) has been used as a means to facilitate locomotor recovery in spinal cord injured humans. Electrode arrays, instead of conventional pairs of electrodes, are necessary to investigate the effect of ESCS at different sites. These usually require a large number of implanted wires, which could lead to infections. This paper presents the design, fabrication and evaluation of a novel flexible active array for ESCS in rats. Three small (1.7 mm(2)) and thin (100 µm) application specific integrated circuits (ASICs) are embedded in the polydimethylsiloxane-based implant. This arrangement limits the number of communication tracks to three, while ensuring maximum testing versatility by providing independent access to all 12 electrodes in any configuration. Laser-patterned platinum-iridium foil forms the implant's conductive tracks and electrodes. Double rivet bonds were employed for the dice microassembly. The active electrode array can deliver current pulses (up to 1 mA, 100 pulses per second) and supports interleaved stimulation with independent control of the stimulus parameters for each pulse. The stimulation timing and pulse duration are very versatile. The array was electrically characterized through impedance spectroscopy and voltage transient recordings. A prototype was tested for long term mechanical reliability when subjected to continuous bending. The results revealed no track or bond failure. To the best of the authors' knowledge, this is the first time that flexible active electrode arrays with embedded electronics suitable for implantation inside the rat's spinal canal have been proposed, developed and tested in vitro.

An Implantable Versatile Electrode-Driving ASIC for Chronic Epidural Stimulation in Rats.

This paper presents the design and testing of an electrode driving application specific integrated circuit (ASIC) intended for epidural spinal cord electrical stimulation in rats. The ASIC can deliver up to 1 mA fully programmable monophasic or biphasic stimulus current pulses, to 13 electrodes selected in any possible configuration. It also supports interleaved stimulation. Communication is achieved via only 3 wires. The current source and the control of the stimulation timing were kept off-chip to reduce the heat dissipation close to the spinal cord. The ASIC was designed in a 0.18- µm high voltage CMOS process. Its output voltage compliance can be up to 25 V. It features a small core area (<;0.36 mm(2)) and consumes a maximum of 114 µW during a full stimulation cycle. The layout of the ASIC was developed to be suitable for integration on the epidural electrode array, and two different versions were fabricated and electrically tested. Results from both versions were almost indistinguishable. The performance of the system was verified for different loads and stimulation parameters. Its suitability to drive a passive epidural 12-electrode array in saline has also been demonstrated.