Silicon integrated circuits (ICs) are central to the next-generation miniature active neural implants, whether packaged in soft polymers for flexible bioelectronics or implanted as bare die for neural probes. These emerging applications bring the IC closer to the corrosive body environment, raising reliability concerns, particularly for chronic use. Here, we evaluate the inherent hermeticity of bare die ICs, and examine the potential of polydimethylsiloxane (PDMS), a moisture-permeable elastomer, as a standalone encapsulation material. For this aim, the electrical and material performance of ICs sourced from two foundries was evaluated through one-year accelerated in vitro and in vivo studies. ICs featured custom-designed test structures and were partially PDMS coated, creating two regions on each chip, uncoated “bare die” and “PDMS-coated”. During the accelerated in vitro study, ICs were electrically biased and periodically monitored. Results revealed stable electrical performance, indicating the unaffected operation of ICs even when directly exposed to physiological fluids. Despite this, material analysis revealed IC degradation in the bare regions. PDMS-coated regions, however, revealed limited degradation, making PDMS a suitable IC encapsulant for years-long implantation. Based on the new insights, guidelines are proposed that may enhance the longevity of implantable ICs, broadening their applications in the biomedical field.@en

Miniaturization of next-generation active neural implants requires novel micro-packaging solutions that can maintain their long-term coating performance in the body. This work presents two thin-film coatings and evaluates their biostability and in vivo performance over a 7-month animal study. To evaluate the coatings on representative surfaces, two silicon microchips with different surface microtopography are used. Microchips are coated with either a ≈100 nm thick inorganic hafnium-based multilayer deposited via atomic layer deposition (ALD-ML), or a ≈6 µm thick hybrid organic–inorganic Parylene C and titanium-based ALD multilayer stack (ParC-ALD-ML). After 7 months of direct exposure to the body environment, the multilayer coatings are evaluated using optical and cross-sectional scanning electron microscopy. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is also used to evaluate the chemical stability and barrier performance of the layers after long-term exposure to body media. Results showed the excellent biostability of the 100 nm ALD-ML coating with no ionic penetration within the layer. For the ParC-ALD-ML, concurrent surface degradation and ion ingress are detected within the top ≈70 nm of the outer Parylene C layer. The results and evaluation techniques presented here can enable future material selection, packaging, and analysis, enhancing the functional stability of future chip-embedded neural implants.

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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 article. 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× 200 μ m 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 VN without requiring intraneural implantation.

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This study explores the application of a novel transfer-free method for the synthesis of multilayer Chemical Vapour Deposition (CVD) graphene directly on transparent sub-strates, specifically to create transparent Microelectrode Arrays (MEAs) for optogenetic studies. Traditional methods typically involve a graphene transfer step that can compromise the material's integrity and electrical properties. By eliminating this step, our approach simplifies the fabrication process. The developed MEAs were characterised by Raman spectroscopy, op-tical transmittance, and electrochemical impedance spectroscopy. We also assessed the stability and recording capabilities of the fabricated MEAs, alongside a comparative assessment with a commercial MEA. Turbostratic graphene grown directly on quartz and sapphire was successfully achieved. Our transfer-free MEAs exhibit promising signal detection capabilities, despite a relatively high baseline noise of ∼ 23μ V. and a significantly large impedance at 1 kHz (3.2 to 9.89 M Ω) surpassing values in other studies. The devices exhibited low stability after exposure to liquid media during the soaking and ageing tests, causing large variations in the electrochemical measurements post-exposure. This was due to the permeability of the encapsulation layer and the biodegradability of the molybdenum structures, which led to significant structural and chemical changes in the devices. While further work is required to prevent the failure mechanisms of the device, this study demonstrates the feasibility of transparent MEA fabrication by means of a transfer-free approach directly on quartz substrates.

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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.@en

Implantable devices need to communicate information to the outside world. For deep-seated miniaturized implants ultrasound communication can be favourable. However, implants need to operate during movement, and the selected communication scheme should be assessed accordingly. In this work, we implemented a simple protocol to transfer data packets based on On-Off-Keying (OOK) and Frequency-Shift-Keying (FSK) by backscatter modulation in ultrasonic communication links for deep implants.We then used it to compare FSK vs OOK encoding regarding the bit error rate during continuous ultrasound power transfer, and while moving, in a water tank setup. Our experiment shows, that sub-millimeter movements can have severe effects on OOK communication, but not for FKS. Therefore, FSK can allow for backscatter communication from deep implants regardless of their position and involved movements. The protocol can also be adapted to other backscatter modulation schemes in the future. @en

Aluminum Nitride (AlN) Piezoelectric Micromachined Ultrasonic Transducers (PMUTs) are gaining interest for biomedical implant power due to biocompatibility and lowtemperature processing. However, due to the low piezoelectric coefficient of AlN PMUTs, storage capacitors are often used to accumulate ultrasonic power transferred over an extended time. The accumulated energy is then used to power a DC load, which leads to a long start-up time, and insufficient duty cycle for some applications. We present an ultrasonically powered system for biomedical implants capable of delivering mW-range instantaneous power to DC loads, without pre-storing it. The system features a 25 mm2 AlN PMUT, an inductive matching network, and an application-specific power management integrated circuit(ASIC). For an acoustic intensity of 360 mW/cm2 at the surface of the PMUT, an open-circuit voltage of 1.11 V and an aperture efficiency of 30.5 % are measured. Furthermore, by connecting a series-matching inductor to the PMUT, the highest-reported power delivered to the load (PDL) of 6.4 mW is measured over an optimal load of 7.6 Ω. Finally, together with the ASIC and at the intensity of 108 mW/cm2, our system delivers 1.04 mW DC power to a 3.3 kΩ load, which is over two orders of magnitude higher than the previously reported average DC power for AlN PMUTs. @en

In the domain of ultrasonically powered biomedical implants, there is an increasing interest in cm-scale ultrasonic receivers (RX). However, when a single-element transducer is used as the RX transducer, an uneven phase distribution across the RX area can significantly reduce the harvestable power. In this paper, we investigate the impact of lateral and angular misalignment on the acoustic field phase distribution across the RX surface. We show that, for a single-element RX transducer, lateral misalignment has minimal effect on the harvestable power, whereas even small angular misalignments can cause a considerable reduction, especially for larger RX sizes. We present a potential solution that consists of subdividing a large RX transducer (e.g. 20 × 20mm2) into smaller elements, which significantly improves power transfer efficiency by taking advantage of the smaller phase variation across the surface of each element. The trade-offs between achieving a minimum acceptable power transfer efficiency and managing the increased complexity in packaging and matching circuitry are also discussed. @en

This paper presents a novel multi-channel stimulation backend with a multi-bit delta-sigma control loop, which enables precise adjustment of the stimulation current through modulation of the supply voltage. This minimizes the overhead voltage of series circuitry to the stimulation load and avoids the associated energy loss. Additionally, to address the bandwidth limitations commonly encountered in battery-less implants, we propose incorporating amplitude and duration scaling of the arbitrary stimulation waveform. The waveform is programmable with 64 7-bit samples and 4 scaling factors per channel, resulting in a minimum of 68% data reduction per channel compared to using the waveform without scaling. The proposed circuits are designed and simulated in 180nm BCD technology occupying a total silicon area of 9mm2. The fully integrated backend has a minimum compliance voltage of 8.5V and features a switched-capacitor multi-output DC-DC converter (MODDC) with pulse-skipping capability, a CMOS-only high-voltage (HV) multiplexer, and a unique HV H-bridge. Programming a sine-wave stimulus with a 4mA amplitude and a duration of 256μs achieved a signal-to-noise ratio of 40dB within a 10kHz bandwidth. For the same waveform, power efficiencies of 94% and 68% were observed without and with MODDC, respectively. Additionally, when programming constant-current stimuli ranging from 0.26mA to 4mA, high efficiencies of 78-97% and 23-79.4% were achieved without and with MODDC, respectively.@en

Capacitive Micromachined Ultrasound Transducers (CMUTs) have many advantages compared to other ultrasonic transducer technologies, especially for implantable devices. However, they require a high bias voltage for efficient operation. To eliminate the need for an external bias voltage, a charge storage layer can be embedded in the dielectric. This study aims to compare the performance of Si 3 N 4 and Al 2 O 3 when used as a charge storage layer. By measuring the shift in the C-V curve, Si 3 N 4 exhibits a larger shift than Al 2 O 3 , indicating a better charge-trapping capability. When using the pre-charged CMUTs as power receivers, the Si 3 N 4 version harvested up to 80 mW -only a few mW more than the Al 2 O 3 - with an efficiency of about 50 %. Accelerated Lifetime Tests predict a lifetime of about 7.8 and 1.2 years for Si 3 N 4 and Al 2 O 3 respectively.@en

Safety is a critical consideration when designing an electrical neural stimulator, given the direct contact with neural tissue. This paper presents the design of a charge balancing system suitable for frequencies up to the kilohertz domain, to be used as an add-on system for stimulators over a wide range of frequencies, also covering nerve conduction blocking. It operates independently of the stimulator timing by continuously sensing the offset voltage, and applying a corrective current to the electrode, using the offset compensation technique. To ensure its stand-alone capability, the system is battery-powered, and includes a safety and start-up circuit. Electrical measurements verified the functionality of the circuit, demonstrating a residual offset of only 0.7 mV for 1 V biphasic pulses at 50 kHz. When tested for 20 kHz biphasic pulse at a 5 V amplitude, the offset was measured at -11.6 mV, which is still within the (commonly used) ±50 mV safety window.@en

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.@en

Electrical stimulation is proven to be an effective way of neuromodulation in bioelectronic medicine (e.g. cochlear implants, deep brain stimulators, etc.), delivering localized treatment by the means of electrical pulses. To increase the stimulation efficiency and neural-type selectivity, there is an increasing interest to employ non-rectangular stimulation waveforms [1-4]. Even though delivering and storing digital data at the stimulator provides the highest flexibility for generating stimulation waveforms, state-of-the-art approaches suffer either from poor resolution or the requirement of high data bandwidth for wirelessly powered implants [2]. Using Analog waveform generators is an alternative approach at the cost of extra implementation complexity for each type of waveform [3]. To fulfill the same goals as employing arbitrary waveforms for stimulation, we propose to shape the typical rectangular waveform using a programmable first-order low-pass filter, mimicking the natural filtering characteristic of the neural membrane. Using bio-realistic modeling, we show that such a pre-filtered waveform requires less or equal energy for the activation of neurons when compared with other energy-efficient waveforms (e.g. Gaussian). Notably, this comes at the low cost of only one extra programmable parameter (i.e., the filter’s corner frequency), on top of the typical duration and amplitude parameters. The basic concept of this work is driven by the fact that the natural low-pass characteristic of the neuron’s membrane limits the energy transfer efficiency from the stimulator to the cell. Thus, it is proposed to pre-filter the high-frequency components of the stimulus [4]. The method is validated for a Hodgkin-Huxley (HH) axon-cable model using NEURON v8.0 software. The required activation energy is simulated for rectangular, Gaussian, half-sine, triangular, ramp-up, and ramp-down waveforms, all with pulse durations of 10-1000µs, and low-pass filtered with cut-off frequencies of 0.5-50kHz. Simulations show a 51.5% reduction in the required activation energy for the shortest rectangular pulse (i.e., 10-μs pulse width) after filtering at 5kHz. It is also shown that the minimum required activation energy can be decreased by 11.04%, 9.49%, 8.28%, 1.81%, 0.17%, and 0% when an appropriate pre-filter is applied to the rectangular, ramp-down, ramp-up, half-sine, triangular, and Gaussian waveforms, respectively. Finally, a perspective usage of this method to improve the selectivity of electrical stimulation is drawn. @en

This paper presents a new communication method between micro-scale freely floating brain implants based on galvanic coupling (GC), called "Brain-Coupled Communication" (BCC). Since the transmission efficiency based on GC is highly dependent on the system’s geometry and the electromagnetic properties of the tissue, finite element models in COMSOL Multiphysics® are employed for characterizing the proposed method. Concurrent scaling of channel length (i.e., the distance between two implants), the inter-electrode distance (on a single implant), and electrode dimensions with a constant ratio down to 2 % of their typical values show an increase in the optimum frequency of the communication by 50 times (from 200 kHz to 10 MHz). This, in turn, yields a substantial increase in the channel bandwidth. The proposed method also shows excellent robustness against misalignment. Up to 60 ° of angular misalignment and 1 mm of lateral displacement result in a voltage-gain attenuation of less than 5 dB and 2 dB, respectively. Furthermore, a negligible shading effect between implants is observed by exploring multi-implant scenarios. Moreover, based on the conducted compliance study, no safety hazards were observed for the intended conditions. In conclusion, the proposed method exhibits a multitude of desirable qualities that position it as an excellent choice for establishing a network of freely floating brain implants.@en

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.@en

Micromachined Ultrasonic Transducers (MUTs) are being explored as power converters in wirelessly powered biomedical implants. This paper investigates the role of mechanical support properties in piezoelectric MUTs (PMUTs) on their power conversion efficiency. For this purpose, a finite element model (FEM) of a PMUT array was developed and integrated with an equivalent circuit model (ECM). The study considered different mechanical support scenarios, from rigidly clamped to completely free. These were numerically analyzed and validated by impedance measurements and acoustic power transfer experiments on PMUT prototypes. The results show that reducing the mass of the mechanical support increases the Q factor, leading to a significant improvement in power conversion efficiency, with an efficiency increase factor of 5.6x from the clamped to the free case. This approach can potentially enhance overall power conversion efficiency, reduce the need for matching networks, and enable miniaturization in ultrasonically powered implants.@en

In an attempt to reduce the side effects caused by the chemically-based drugs used to treat neurological disorders, the field of bioelectronics has been focusing on the development of smart and reliable solutions that could, ideally, interact with the tissue at a resolution of individual cells.1 Conventionally, electrically-based systems have been used.2 However, increasing the resolution at which they interact with the body leads to the development of invasive electrode arrays, which can cause long-term side effects.3 Another approach, based on acoustic waves, has recently emerged. Ultrasound (US) neuromodulation has been proven to be effective in modulating the response of peripheral nerves, in an in-vivo setup4 and has the potential to achieve higher spatial selectivity.5 In this work, we aim to fabricate an implantable cuff for US neuromodulation, which would employ an array of US transducers to deliver focused US to specific nerve areas in a non-invasive manner. To this end, the potential of different US transducer arrays for peripheral nerve applications is evaluated, assessing the acoustic performances as well as ease of assembly and integration. More specifically, two of the most important parameters that affect neural excitation are the frequency and output pressure generated by the US transducers.4 Conventional bulk PZT transducers can generate a wide range of output pressures but these are not small enough for this application. PZT-based arrays, integrated on CMOS have recently emerged, and will be part of this evaluation6. However, these have not yet been integrated on flexible substrates. On the other hand, micromachined US transducers (MUTs) have been gaining a lot of interest, particularly capacitive MUTs (CMUTs) which can operate at high frequencies, thus reducing the focal point significantly.5 CMUTs can be fabricated on flexible substrates, using biocompatible materials, rendering them a very attractive candidate for the envisioned cuff. However, CMUTs usually feature lower Q factors compared to PZTs, hence the output pressure still has to be evaluated for neuromodulation. In addition, this work will also discuss important characteristics of the materials used for encapsulation, as these should ensure the required flexibility of the cuff without negatively affecting the acoustic performance of the transducers.@en

During the last few decades, electrical neural stimulators have successfully been employed as a means of treatment for a wide range of neurological disorders. By targeting the peripheral and central nervous systems, electrical neurostimulators activate/inhibit neural activity by manipulating the stimulus- induced electric field arising at the targeted area through diverse electrode configurations. Aiming at reducing the overall size of implanted stimulator systems, these are being designed to be wirelessly powered and batteryless. Technologies for wireless power transfer to implants are mainly based on inductive coupling and, more recently, ultrasonic waves. To increase the power efficiency and thereby minimize the power consumption of the implant, we have previously proposed a stimulation technique that alters the electric field at the tissue by delivering charge in small packets in a very rapid manner (e.g. 1 Mpps). This charge is consequently accumulated by the tissue’s integrating nature.1 This approach removes the need to ensure continuous accurate control of the stimulus current amplitude, resulting in power savings. To the same end, in an ultrasonically powered system, unnecessary power-conversion blocks can be eliminated, as the incoming ultrasonic wave is harvested, converted into an electrical signal, rectified, and then directly used for stimulation.2 Inspired by the above, this work focuses on providing a discrete-component multi-channel neural stimulator, powered wirelessly through ultrasound (US), to activate and inhibit neural activity. The use of mostly commercially available discrete components will ensure reproducibility by other research labs and help provide a platform technology that can be used as an experimental tool in a variety of applications.3 The US pressure wave obtained at the receiving US transducer will be converted into electrical energy and used both for powering the system as well as to shape the charge packets of the eventual stimulus pulse. In this manner, the need for DC-DC up-conversion, typically needed for neuromodulation, will be eliminated.4 A charge-balancing technique, matching the fast pulse repetition rates (PRR) required for inhibition of neural activity (typically ≥ 5 kHz), will ensure the safety of the implant, while the injected charge will be constantly monitored and adapted for safe and efficacious activation/inhibition.@en

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.@en

This work proposes a guideline for designing more energy-efficient electrical stimulators by analyzing the frequency spectrum of the stimuli. It is shown that the natural low-pass characteristic of the neuron’s membrane limits the energy transfer efficiency from the stimulator to the cell. Thus, to improve the transfer efficiency, it is proposed to pre-filter the high-frequency components of the stimulus. The method is validated for a Hodgkin-Huxley (HH) axon cable model using NEURON v8.0 software. To this end, the required activation energy is simulated for rectangular pulses with durations between 10 µs and 5 ms, which are low-pass filtered with cut-off frequencies of 0.5-50 kHz. Simulations show a 51.5% reduction in the required activation energy for the shortest pulse width (i.e., 10 µs) after filtering at 5 kHz. It is also shown that the minimum required activation energy can be decreased by 11.04% when an appropriate pre-filter is applied. Finally, we draw a perspective for future use of this method to improve the selectivity of electrical stimulation.@en