For over five decades, electronic implants have significantly improved the quality of life for millions of patients. With their great potential, substantial advancements have been made in developing new therapeutic devices, particularly in the fields of bioelectronic medicine and brain-machine interfaces. However, these emerging devices require novel approaches to packaging, as traditional hermetic enclosures no longer meet the physical and dimensional demands of modern systems. Polymer packaging offers a promising alternative, enabling device miniaturization and facilitating minimally invasive procedures. Polymer packaging was in fact one of the earliest methods used to protect electronics (implemented with discrete components) in the body. However, due to the inability of polymers to fully block moisture ingress, it soon became evident that the body’s wet and corrosive environment could negatively impact device longevity. As electronic implants evolved from using discrete components to complex integrated circuits (ICs), the challenge of protecting these devices became even more critical. In this thesis, I aimed to tackle the challenge of ensuring the safe and reliable operation of polymerpackaged ICs for long-term implantable applications. To address this challenge, I pursued three key objectives: 1) I developed on-chip sensor platforms to carefully monitor the integrity of the IC structure. These tools provide critical data on the condition and performance of the chips, ensuring their expected functionality in clinical settings. 2) I investigated the electrical and material stability of IC structures by directly exposing them as bare die (uncoated) to physiological environments, assessing their durability in the body’s corrosive conditions. By identifying potential degradation pathways, I proposed IC design guidelines that can potentially enhance the longevity of polymerpackaged devices. 3) I investigated if silicone rubber, as a polymer packaging material, could prevent or slow down the degradations seen in uncoated ICs. Separately, I also evaluated two thin-filmpackaging layers for their effectiveness in IC protection. Results demonstrated that IC structures can be inherently hermetic, enabling polymers, such as silicone, to serve as standalone packaging materials despite their moisture permeability. Furthermore, silicone was found to effectively prevent the degradations observed in bare-die ICs. Using advanced material analysis techniques, I derived degradation rates, showing that silicone-encapsulated ICs could last over 10 years in the body. These findings enable the development of long-lasting miniature implants, reducing the need for repeated surgeries and improving patients’ quality of life.@en

Characterizing electrodes for neural interfaces is an essential step of the prototyping and manufacturing process. Sample performance can be modelled by conducting electrochemical measurements such as Electrochemical Impedance Spectroscopy, Cyclic Voltammetry, Voltage Transients and Noise characterization, providing insights for future use scenarios. However, parameters, techniques, and scientific reporting of results often fall short of a complete characterization and do not adhere to any standard.

A platform for accurate, reliable, and standardized electrode characterization was conceived to overcome these obstacles. It allows complete electrochemical characterization while providing a modular 3D-printed solution to securing the electrodes above the beaker. Additional parameters, such as electromagnetic isolation and control of the medium, are also accounted for. A complete characterization study of ENEPIG electrodes was carried out to validate the setup. Manufactured as circuit boards, not electrodes, several aspects of their electrochemical performance were lacking - mainly their survivability to the stress applied by the tests carried out. Testing parameters had to be determined to minimize structural damage while maximizing performance, akin to what would be desirable in a clinical setting.

Sensing characterization experiments identified a double-layer electrode structure and revealed that smaller electrodes exhibit capacitive behaviour in bandwidths one order of magnitude wider than larger ones. Stimulation characterization experiments ascertained that charge surface distribution would predominantly accumulate along the perimeter of the electrode. In conjunction with surface characterization, results indicate the flat surface of the electrodes prevents charge from being stored and injected optimally. Ultimately, the performance of the ENEPIG electrodes was measured with the injection-to-storage ratio at 10%, significantly inferior to other Au electrodes reported in the literature and utilized in vivo. As results accurately represented the sample population, characterization was deemed successful - validating the experimentation setup developed for this project.

Electronic interfaces, particularly microelectrode arrays (MEAs), are crucial for studying electrophysiological processes in the body, with applications ranging from implants to deep brain simulators. In neuroscience, they play a vital role in exploring neuronal cell distribution and behaviour, as well as disorders like epilepsy and Alzheimer’s disease. However, electrophysiological recordings have limitations, that have led to the exploration of optical approaches like calcium imaging. To address the shortcomings, a promising strategy involves integrating electrophysiology and optical methods for simultaneous cellular activity measurement, capitalising on their combined temporal and spatial resolution. The challenge lies in developing fully transparent MEAs to overcome the limitations of traditional opaque electrodes.
Graphene’s versatile properties, spanning from electrical conductivity to mechanical flexibility, position it as an ideal material for transparent and flexible electronics, particularly in neural recording and stimulation. Due to these properties, graphene MEAs (gMEAs) allow integration with various optical techniques, overcoming limitations associated with traditional opaque MEAs.
In this project, we designed and fabricated a transparent gMEA, intended to perform electrical signal recordings and optical voltage mappings simultaneously from photostimulated optogenetic cell lines. The design allows for photostimulation from a source beneath the gMEA, while enabling unobstructed optical measurements from above. The electrodes were crafted from multilayer chemical vapour deposition (CVD) graphene, chosen for its transparency and favourable electrical properties. Quartz and sapphire were evaluated as potential substrates for the device. After demonstrating the synthesis of multilayer graphene was possible on both substrates, quartz was selected as the preferred material due to its resistance to graphene delamination.
Characterisation of the gMEAs was done using various techniques, including optical transmittance (OT), electrochemical impedance spectroscopy (EIS), and measurements of the signal-to-noise ratio (SNR). The stability of the gMEAs was also assessed by immersing the devices in cell culture medium and with ageing tests performed in PBS. Initial electrochemical characterisation of the gMEAs exhibited promising signal detection despite a relatively high baseline noise of ∼ 23 μV . In comparison, commercially available MultiChannel Systems MEA (60MEA200/30iR-Ti), showed a lower baseline noise (∼ 4 μV ), but gMEAs achieved comparable signal sensitivity. EIS of gMEAs revealed an impedance at 1 kHz ranging from 3.2 to 9.89 MΩ, largely surpassing values in other studies. However, when area normalised, the impedance remained comparable to reported values. Stability tests identified issues related to the permeability of the encapsulation layer and degradation of molybdenum structures, causing large variations in the SNR and EIS measurements after exposure to liquid media.

Resolving the underlying mechanisms of complex brain functions and associated disorders remains a major challenge in neuroscience, largely due to the difficulty in mapping large-scale neural network dynamics with high temporal and spatial resolution. Multimodal neural platforms that integrate optical and electrical modalities offer a promising solution, with microelectrode arrays (MEAs) being particularly effective for capturing electrophysiological activity across multiple neurons at the cellular level. Graphene has emerged as a highly attractive material for such neural interfaces due to its unique combination of biophysical, electrical, mechanical, biological, and optical properties. However, current graphene-based electrodes face challenges, including the need for transferring pre-grown graphene layers, which causes reliability issues.

In this work, microelectrode arrays based on transfer-free multilayer graphene and PEDOT:PSS are developed, and their feasibility for in vitro neural activity detection is evaluated through a brain slice culture. Firstly, the design and fabrication of graphene-based MEAs (grMEA) on transparent substrates is presented, establishing optimized microfabrication procedures for the integration of transfer-free multilayer graphene technology on in vitro MEAs. Several electrode diameters, ranging from 10 μm to 500 μm, are included to accommodate different experimental requirements and test the limits of the technology. Second, the combination of graphene and PEDOT:PSS conductive polymer is explored to overcome the fundamental limitations associated with graphene electrodes, such as high impedance at small electrode sizes, without compromising the optical transparency. A technique to integrate patterned PEDOT:PSS polymer coating on the electrodes to form graphene/PEDOT:PSS microelectrodes
(grppMEA) is developed.

The electrochemical performance, including charge storage capacity (CSC) and impedance properties, of the grMEA and grppMEA devices are evaluated. Obtained results, comparable with state-of-the-art neural interfaces, show that the PEDOT:PSS coating increases CSC values more than the double and substantially reduces the impedance by 10-20 times (e.g., from 247 kΩ to 13 kΩ for 50 μm diameter electrodes). This demonstrates the potential of the devices for efficient electrical coupling with neural tissue. Additionally, the volumetric capacitance of grppMEA electrodes was found to be 55.7 F/cm3, highlighting the volumetric ionic-electronic interaction coming from the PEDOT:PSS film, a feature absent in metal electrodes.

A custom-made interface that effectively connects the MEA devices to specific recording systems is developed to enable the acquisition of neural signals. The electrophysiological recording capabilities of the grMEA and grppMEA devices were subsequently evaluated through in vitro cerebellar brain slice cultures. Acute recordings of spontaneous activity and spike pattern characteristics of Purkinje cells and other neurons have been successfully obtained. The obtained signal-to-noise ratio values, ∼ 30 dB, demonstrate the great recording potential of the proposed MEAs. Overall, the results presented in this work demonstrate that transfer-free multilayer graphene MEA technology, especially when combined with PEDOT:PSS, overcomes the current limitations and offers the possibility for high-density recordings with single-cell resolution.

Graphene-based neural interfaces offer an innovative solution to surpass the resolution limit of traditional neural recording, integrating neuroelectronics with optogenetics for combined electrophysiological and optical neural monitoring, among others. Three important factors in these interfaces are achieving a high signal-to-noise ratio (SNR), maintaining effective stimulation properties, and ensuring strong cell adhesion to neural tissue, which can be enhanced through surface topography modifications. This work explores two main approaches to enhance graphene-based neural interfaces: (1) exploring the creation of thin graphene films on molybdenum to integrate transistors and electrodes within a single fabrication process, which can potentially enhance the signal-to-noise ratio (SNR) while maintaining stimulation efficacy; and (2) creating corrugated graphene structures that increase surface area and improve cell adhesion. A major challenge in this work is establishing a transfer-free chemical vapor deposition (CVD) process on molybdenum for both approaches. While this method offers significant benefits, such as reducing defects and contamination, the challenge lies in the limited understanding of the mechanisms behind graphene growth on this catalyst. Exploring new molybdenum configurations to provide a better understanding of the graphene growth mechanism on this catalyst is also a relevant part of this work.
Experiments revealed that graphene grown on thick, unpatterned molybdenum produced high quality few layer graphene (FLG), while patterned thick molybdenum produced multilayer structures with high defect density. Based on the results obtained, a mechanism for graphene growth on thick molybdenum catalysts is proposed. However, the decision was made to proceed with the second research approach due to time limitations. Considering corrugated graphene structures, Raman analysis showed higher-quality graphene layers within the valleys, fact that supports the proposed growth model. sheet resistance values ranged from 60 Ω/sq – 180 Ω/sq, being these values among the lowest reported in the literature for undoped graphene. These low values are attributed to the combination of an FLG graphene with good interlayer electronic coupling, which is possible because of the low number of defects in the material. Results are promising for enabling high-density optically transparent neural interfaces with graphene tracks. Additionally, small and denser corrugations enhanced the electrode surface area, showing reduced impedance at 1 kHz compared to flat electrodes. Electrodes with 1 μm, 5 μm, and 20 μm corrugations shown impedance reductions in comparison to flat electrodes, demonstrating an increased surface area. The area normalized impedance decreased from 35.5 kΩ ± 0.7 kΩ for flat electrodes to a minimum of 26.2 kΩ ± 1.1 kΩ. The electrodes achieved a maximum charge storage capacity (CSC) of 80.6 μC/cm2 and a maximum charge injection capacity (CIC) of 7.71 μC/cm2, which are lower than the threshold for stimulation applications. However, these values could be potentially optimized through fabrication refinement. Furthermore, the biocompatibility tests indicated that corrugated graphene patterns are biocompatible have the potential to actively influence stem cell cytoskeleton dynamics, highlighting their promise as a safe and novel inclusion in interfaces for next- generation neural applications.

Advancements in healthcare technology are driving innovation through the decentralization and personalization of medicine. The convergence of Pharma, MedTech, and ECS industries has led to new medical domains, including bioelectronic medicines and personalized ultrasound. Ultrasound, particularly through Micromachined Ultrasonic Transducers (MUTs), is a key technology in these fields. MUTs, which include CMUTs (Capacitive Micromachined Ultrasonic Transducers) and PMUTs (Piezoelectric Micromachined Ultrasonic Transducers), offer benefits over traditional PZT transducers, such as lower costs and the absence of toxic materials.
This thesis focuses on pre-charged collapse-mode CMUTs, which operate without a DC bias voltage, making them suitable for in-body applications. This is achieved by embedding a charge storage layer in their dielectric. The research involved designing and testing a first and second generation of CMUTs with different charge storage layers. The second generation showed improved performance and comparable results to standard externally biased CMUTs.
The primary application explored was using pre-charged CMUTs as ultrasonic power receivers for implantable devices. The impact of lateral and angular misalignment on power efficiency was studied, with angular misalignment being most detrimental. Solutions proposed included decreasing the frequency, partitioning the receiving transducer, and using a beamforming algorithm.
Experimental evaluations showed power conversion efficiencies up to 80% with optimal load and about 50% with a resistive load at 2.5 MHz. These efficiencies are comparable to those achieved with PZT transducers but with better biocompatibility.
Finally, the thesis demonstrated the functionality of the first ultrasonically powered implantable device using pre-charged CMUTs for battery charging. The device achieved a total system efficiency of 21%, significantly better than other implantable devices using PMUT or PZT transducers.
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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) piezoelectric ultrasound transducers is proposed. 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 piezoelectric ultrasound transducers. A focal spot size of 200 μm by 200 μm is measured for the proposed cuff. Moreover, the curvature of the device leads to constructive interference of the ultrasound waves originating from multiple piezoelectric ultrasound transducers, which in turn leads to an increase of 45% in focal pressure compared to the focal pressure of a single piezoelectric ultrasound transducer. Integrating piezoelectric ultrasound transducers in an extraneural cuff-shaped design has the potential to achieve high-precision ultrasound neuromodulation of the Vagus Nerve without requiring intraneural implantation.

Electrical stimulation has emerged as a promising therapeutic modality for the treatment of various neurological disorders such as Parkinson's disease, chronic pain, epilepsy, and depression. In addition, recent studies have provided evidence supporting the effectiveness of electrical stimulation as a treatment option for patients with chronic migraine and cluster headaches who have been unresponsive to other therapies. Specifically, stimulation of the occipital and supraorbital nerves has shown promise in managing these refractory conditions. Current implantable medical devices (IMDs) are battery-powered, which increases the size of the implant and involves lengthy wires to connect with the electrodes. Wireless power transfer (WPT) techniques can be used to reduce the size and omit the battery from the implants. However, conventional power management methods use a rectifier, power converter, and neurostimulator to convert the AC power of the link to DC power and provide electrical stimulus, which lowers implant power efficiency.

This thesis presents a novel neurostimulator circuit that salvages and stores available energy from an inductive link. The circuit design includes an inductor for energy storage and utilizes a buck-boost converter-like topology to deliver the stored energy to the tissue. This topology exploits the capacitive membrane's characteristics and injects the charge into the tissue through ultra-high frequency pulsed stimulation without requiring additional circuits that may contribute to power losses. Operating at the resonance frequency of 6.58MHz, the circuit was designed and simulated to inject approximately 500nC at an 18mm distance from the transmitter. Furthermore, the proposed circuit design incorporates a charge-metering circuit adapted to ensure stimulation efficacy in response to coupling variations. To guarantee safety during stimulation, the residual voltage is carefully monitored and brought close to zero at the end of each stimulation cycle. To achieve this, a charge-balancing scheme has been implemented, which utilizes a comparator to monitor the residual voltage across the electrode.

The proposed circuit was designed on a printed circuit board (PCB) to evaluate its feasibility. To evaluate its performance, a signal generator was used to simulate the input of the inductive link, and an electrode-tissue interface (ETI) model was used at the output. The circuit demonstrated its efficacy in measuring the charge and reducing the residual voltage within established safety limits while maintaining energy efficiency. More specifically, the charge metering measured a charge of 404nC for 450nC of injected charge, which is a 10.22% of error. Moreover, the circuit exhibited a linear response in controlling the injected charge. In the tested range, the charge balancing scheme yielded residual voltages ranging from -20mV to -16mV. The effectiveness of the charge balancing scheme was further confirmed through in-vitro measurements in a phosphate-buffered solution, with residual voltages measuring at -20mV, which falls within the safe range. Finally, the implemented circuit achieved a peak efficiency of 56%.

Numerous advancements have been made in transparent electrode technologies that can complement optogenetics and imaging modalities. However, several obstacles restrict the design and material of electrode devices, including the required flexibility, transparency, low impedance, high charge storage
capacity (CSC), and high charge injection capacity (CIC), among others. The impedance of transparent graphene arrays is higher, and its CIC is significantly lower than platinum, a metal typically employed for electrophysiological recording and stimulation. It is possible to enhance the electrochemical properties
of planar, transparent graphene electrodes by functionalizing their surfaces with platinum nanoparticles (Pt NPs), effectively increasing the electrode surface area. Existing research on platinum nanoparticles on transparent graphene electrodes has solely focused on simultaneous electrical recording and optical imaging of neuronal activity. There is currently no quantitative evidence of the extent to which platinum nanoparticles can impact the stimulating properties of transparent graphene electrodes and any indication of the stability of the coating. Therefore, material and electrochemical device characterizations were conducted to compare the recording and stimulating properties of graphene versus graphene with Pt NPs of varying surface densities.

Treatment of diseases, illnesses or disorders are always sought without any undesired side-effects and complications. Neurological disorders, such as Epilepsy and Parkinson’s, are currently treated using pharmaceuticals. However, drugs have a low specificity and lose their effectiveness after several years. In addition, prolonged drug usage often leaves patients with many side-effects and complications. Development in neuroscience indicate the treatment of such neurological disorders via neuro-stimulation. Currently, research in understanding the mechanisms behind neuronal stimulation is carried out by research institutes all around the globe. There are three modes for neuronal stimulation, electrical, optical and lastly the use of ultrasonic waves. As optogenetics provides a more specific technique in neuronal stimulation and electrical recording can provide high spatial resolution data, it is sought to combine this two modes.
This work reports the development of a monolithically fabricated active implant, with optogenetic compatibility using transfer-free graphene electrodes. To achieve this desired goal, a microfabrication process is developed, which is reproducible and scalable with modern day microfabrication technology. In order to be compatible with optogenetics, graphene electrodes are used, as these are transparent and allow for neuronal stimulation using light. The graphene electrodes are grown on a pre-defined molybdenum catalyst, allowing for a transfer-free chemical vapor depostion (CVD) of graphene. Microelectrode-arrays (MEAs) are developed, using graphene electrodes, that include different sized electrodes and different amount of electrodes. The amount being constrained by the available space on the cortex of a mouse.
The aim of this work was to be able to control or read out these MEAs using electronics developed alongside the electrodes. As graphene is grown at a temperature above the melting point of aluminium, conventional CMOS technology can not be used in combination with graphene electrodes. The process developed, did not include any materials which would be damaged during the graphene growth. The metal gate is replaced by a polysilicon gate and the metal interconnects connecting the active devices and the MEAs are defined after the growth of graphene. Resulting in an active implant which is monolithically fabricated in combination with a transfer-free graphene process.
Monolithically fabricating an active graphene based implant, comes with complications. Delamination of the passivisation layer occurred whilst trying to open contact openings to and from the active devices. This was resolved using a more appropriate chemical etchant.
A fully monolithically fabricated active graphene-based implant was obtained. Electrical measurements showed that the active devices did not behave as expected. Revisiting simulations, it was established that there was leakage of dopants from the gate to the channel. This results in the NMOS devices to be always on and the PMOS devices to have a higher threshold voltage.
However, this particular wafer, had many high temperature steps after the doping of the polysilicon. Reduction of these high temperature steps result in less doping getting into the channel. Alternatively, a thicker gate oxide can be used, to serve as a more robust barrier. A last proposed solution is the reduction of the doping concentration and doping energy of the polysilicon, which would result in less dopant being near the gate oxide interface and thus less dopant leaking into the channel.
There are wafers included in this work with less high temperature steps. However, due to time limitation it was not possible to finish production of these wafer in order to confirm it experimentally. Nevertheless, it is believed that with minor adjustments, this research project is a viable foundation for active graphene based implants and structures.

Neuroscientists use neural electrodes to explore the working mechanisms of the nervous system. Therefore, ideal electrodes should have a small size and the ability to record and stimulate at a single cell resolution with low noise. Materials used for fabrication should be flexible and stable for a long period in the biological media. However, conventional recording and stimulation techniques do not have sufficient spatiotemporal resolution for neuroscience research. Combining electrical and optical modalities into one device helps overcome the resolution limits and record more detailed information. For this application, transparent conductive materials are needed. Graphene is a potential solution due to its advantageous combination of properties, such as high conductivity, transparency, and flexibility. However, important characteristics of recording and stimulation electrodes, such as the impedance and charge injection capacity of graphene electrodes, do not reach the levels of conventional materials. The electrical characteristics of graphene could be improved further with surface modification, chemical doping, or stacking. Each method has been shown to improve the conductivity of graphene, although some affect the transparency of the layer. In this work, three methods were used to improve the electrical characteristics of multilayer graphene neural electrode without losing transparency or flexibility. These methods include growing a thicker layer of graphene, adding metal nanoparticles to the surface of the electrode, and nitric acid doping of graphene. For that purpose, graphene electrodes were fabricated on a silicon wafer. The electrical characteristics of these electrodes were assessed with electrochemical impedance spectroscopy, cyclic voltammetry and 4-point probe measurements. Furthermore, the optical transmittance was measured. The improvement methods were then tested on these electrodes, and the performance was evaluated. Adding metal nanoparticles to the surface of the electrode showed the most promising results. With gold nanoparticles, the impedance at 1 kHz was lowered 82%, and charge storage capacity increased 529%. However, at the same time, 30% of the optical transmittance was lost. With lower nanoparticle density, 6% of transmittance was lost, and 7% of impedance gained. Nitric acid doping did not improve the impedance, but the charge storage capacity was increased up to 66%. Thicker layers of graphene displayed a lower sheet resistance. However, impedance or charge storage capacity were not improved.

Optogenetics is a neuromodulation technique that uses light to control genetically modified cells to express light sensitive ion channels. Optogenetics allows stimulation of only the specific cells in the region that have been genetically modified and thus results in a high resolution of stimulation.
Currently optogenetic implants are used to stimulate specific regions in the brain, either deep in the cortex or on certain regions on the surface of the cortex. An implant with a larger surface area would potentially allow stimulation of the entire cortex simultaneously, if required. By also including recording sites on this implant, it is possible to record responses at one end of the brain produced due to optogenetic stimulation on the other end of the brain. Thus, the underlying neural circuit can be mapped for investigation.
Thin film technology (TFT) so far has had a huge impact in the field of large flexible displays. The flexible substrates and processes employed for the fabrication of flexible displays can be used for the realisation of an optogenetic array that covers the cortex of the brain while being flexible and conformal to the shape of the brain.
This work explores the implementation of TFT in fabricating a flexible large area high-density optogenetic ECoG array. The fabricated array features multi-stacked alternate layers of thin film Au/Ti (for electrodes and interconnects) and thin film SiN (insulation and passivation) on a flexible polyimide substrate to provide a high-density array for improved resolution. Commercial micro-LEDs were bonded to the surface of the array using ICA (Isotropic Conducting Adhesive) to provide on-site stimulation. The resulting flexible implant was characterised to determine the electrode impedance, behaviour of the passivation layer in phosphate buffered saline and thermal characteristics of the micro-LEDs. The final device was implanted on the cortex of a mouse.

Neurostimulation is a common medical treatment modality used to treat neurological disorders. It applies electrical pulses to revert and prevent undesired neural behavior or to create desired neural behavior. The required specificity of said stimulation treatments is oftentimes achieved by implanting the neurostimulator close to the target area. Implantation of active medical device poses a series of challenges and requirements in size and power consumption. Wireless power transfer (WPT) technologies have been used to reduce the size or eliminate the use of batteries, which are the main limiting component in terms of size and longevity of the implants. In conventional WPT systems, the energy must be focused from an external transmitter to a receiver in the implanted neurostimulator. This one-to-one link cannot be used in some applications in which a network of neurostimulators is required to deliver treatment in multiple locations distant from each other. This is the case for some chronic headache treatments in which both the supraorbital and occipital nerves must be stimulated. This thesis proposes a new system level topology for a neurostimulator network for the treatment of chronic headaches, in which all implants are powered through a single WPT link. It was theorized that the bone tissue in the skull can be used as an acoustic conductor for ultrasonic waves, similarly to bone-anchored hearing aid systems that already use bone conduction to conduct acoustic waves in the audible range. Finite element simulations showed that the skull can conduct ultrasonic energy in two frequency bands, which are 0.1-0.6 MHz and 1-2 MHz. A 2 MHz operating frequency was chosen for safety reasons, since the 1-2 MHz band does not leak unwanted energy into neighbouring soft tissues like the brain. At this frequency, the WPT link undergoes an attenuation of about 20 dB. Each individual neurostimulator employs the ultra high frequency (UHF) stimulation technique to improve in power efficiency. Both the UHF stimulation and ultrasonic wireless power transfer work in the MHz frequency range, so the ultrasound signal can be “directly” used for the electrical stimulation of the tissue by means of a simple ultrasound transducer and some power conditioning. Previous designs using this concept are not easily scalable and cannot perform charge balancing to ensure safe stimulation of tissue. In addition, the use of a WPT powering method cannot guarantee a stable and uniform supply for the implanted neurostimulator. As a result, there is a need for a multichannel system that can deliver UHF stimulation pulses in a safe manner, while ensuring efficacy of the stimulation regardless of the power levels received through the WPT link. This thesis proposes a novel output stage for implantable neurostimulators that ensures the efficacy and safety of the stimulation. Since the efficacy is directly related to the total charge delivered to the tissue, a novel charge metering circuitry is designed to control said amount of charge. Safety is obtained by minimizing the residual voltage after a stimulation cycle, which can otherwise damage the tissue and the electrodes. This is done by means of a novel charge balancing scheme that monitors the voltage across the electrodes and stops the stimulation when it crosses 0 V. Circuit simulations successfully validate the design. The proposed neurostimulator was also implemented on a PCB board and tested. The charge delivery resolution of the charge metering circuit is 510 pC. A residual voltage of 0.5-29.5 mV was achieved with the charge balancing circuitry, using an electrical model of the tissue. In vitro measurements in a phosphate buffered saline solution show a 80 mV residual voltage. Hence, this work successfully presents a new neurostimulator output stage topology that ensures efficacy and safety in the presence of an unreliable WPT link, while being compatible with multichannel operation and an IC implementation.

Electronic implants are becoming a valuable tool to explore and regulate neural activity, potentially overcoming neural disabilities that are still incurable. On the one hand, neural recording can provide tremendous insight into the neural system and the sometimes accompanied neural diseases. On the other hand, neural stimulation is necessary to control or adjust neural activity related to neural diseases. Detail of neural recording and stimulation is achieved with highly dense and often deep implantable electrodes (spatial resolution), while neural patterns are found with larger neural area coverage. In both stimulating and recording, a combination of spatial resolution and area coverage can be key to understanding and curing. Application-specific integrated circuits (ASICs) are often employed for the interaction with the electrodes interfacing with neural tissue but ASICs are limited in size, which consequently limits the amount of individual recording or stimulation channels. The de facto solution to circumvent this limitation is to multiplex high numbers of electrodes to a single ASIC channel. However, due to switching and signal latencies only a limited number of electrodes can be multiplexed per channel. Multiple channels on an ASIC are therefore desirable nonetheless to accommodate implants with a many electrodes. Due to recent miniaturization advances, an ever-increasing number of channels can be made available on a single ASIC and the urgency arises to investigate connecting and integrating these channels to electrodes on a flexible implantable substrate. In this work we will investigate technology for assembling a fully flexible electrode array substrate to an ASIC with a high number of channels. For such assemblies, a routing optimiser was developed especially for flexible implants, optimising for chip size and critical substrate limitations. However, with no established manufacturing methodology for such systems, technology parameters were not fully understood. Therefore, initial efforts were put into fabrication of a custom chip with which 72 chip-to-substrate gold stud contacts can be evaluated by means of 4-point measurements and daisy-chaining. This multifunctional chip allows for experiments at various chip-to-substrate contact diameters and pitches. In addition, different materials, including polycarbonate (PC), polyimide (PI) and thermoplastic polyurethane (TPU) were investigated as candidate substrate materials. A transfer methodology, using copper and FR-4 as carrier materials, proved fruitful for these polymeric materials. TPU samples showed particularly promising results, with the main advantage that it can encapsulate the entire implantable system, including chip and metallization, without the formation of additional material interfaces. This has significant advantages for the longevity of implantable systems. A second chip iteration with similar functionality was manufactured with 1008 gold electroplated contacts. The chip measures at 4x4mm² and contacts were designed to be 36x36µm² in size, pitched at 80µm apart. Contact resistances of this chip on TPU substrates were in the range of 5.5 and 73mΩ but the yield of proper contact dropped from 100% to an estimated 90% compared to experiments with the previous chip. A demonstrator product, fully embedded in TPU, was made using the same chip and connects 324 peripheral electrodes to the chip on a single Au metallization layer.

The application of implantable medical devices (IMDs) is increasing rapidly due to the many health benefits they provide in diagnosing and treating diseases. However, these devices have to be able to survive harsh body conditions to ensure their reliability and functionality. Bodily fluids initiate chemical degradation and corrosion in the devices especially in the metal interconnects. Therefore, the devices are encapsulated by various forms of hermetic and non-hermetic packaging. The current standard hermetic packaging is not suitable for miniature microelectronics. As a result, conformal encapsulation is currently being developed. Multiple inorganic and organic layers of materials or a combination of different layers are used to achieve corrosion protection. Polyimide (PI) is a type of polymer that is used as encapsulation material in bioelectronic devices. Recently, there has been an increasing interest in using thin inorganic layers such as SiC and SiO₂ between the polyimide layers in order to improve the PI to PI adhesion. In this thesis, first, the corrosion phenomenon in bioelectronics and the available packaging methods are explained. Next, test structures that contain polyimide encapsulation with and without the SiC and SiO₂ ceramic layers are microfabricated. In order to provide accelerated aging conditions to the samples, a lifetime measurement set-up is modeled and built. Finally, the test structures are tested in the lifetime set-up to evaluate their reliability performances in accelerated aging conditions. The leakage currents of the test structures are measured as a function of the soaking time. Samples with SiC and SiO₂ thin layers exhibit a high leakage current value and fail relatively fast. In addition, samples are analyzed by electrochemical impedance spectroscopy (EIS) measurements and the samples without the ceramic layers demonstrate a capacitive behavior in lower frequencies.

Implantable medical devices (IMDs) such as cardiac pacemakers, cochlear implants, and neurostimulators improve millions of people’s lives every day. Over the years, IMDs have significantly improved in function, increased in lifetime, and decreased in size. However, further miniaturisation is limited by the batteries used to power these devices, and therefore methods to power them wirelessly are gaining in popularity. The technique most used to wirelessly power IMDs is electromagnetic energy transfer. However, at low frequencies, this method is limited to shallow implants due to its low directivity, while at high frequencies it is limited by attenuation in the human body. Therefore, ultrasound energy may be the future of wirelessly powering implants. Its high directivity and low attenuation in the human body opens up the possibility to wirelessly power deep implants without any harmful side effects. An ultrasound energy transfer set-up was established in this work to demonstrate that Philips’ capacitive micromachined ultrasound transducers (CMUTs) can be used as ultrasound energy harvesters. Normally, CMUTs need a bias voltage to function as an energy harvester. However, the CMUTs in this work are chargeable and therefore eliminate the need for this bias voltage. The results show that charged CMUTs can indeed be used as efficient energy harvesters of ultrasound and that information can be sent back to the ultrasound probe using echo modulation. The charged CMUTs showed to be able to harvest sufficient energy to stimulate a nerve and power a Bluetooth module, even when ultrasound sent through 90mm of biological (pork) tissue. The maximum power harvested during the ultrasound energy transfer experiments was 250mW over a transferring distance of 75mm.

The spinal cord, considered to be the most important path of the human body, when injured induces severe motor dysfunction. Therefore, patients affected by lesions on the spinal cord, are most of the time unable to walk, stand or perform motor activities that are trivial for healthy people. To provide a better quality of life for these patients, extensive research and effort have been put by both neuroscientists and engineers to provide clinical therapies for pain relief and locomotion restoration together with dedicated platforms that could deliver these therapies. Currently, for these purposes, epidural spinal cord stimulation is widely used. Apart from being used as a method to reduce pain, it has also been proven to promote locomotion recovery. Apart from clinical trials, it is of great importance to understand the mechanisms that occur while delivering specific therapies. To this end, more exploratory research is mostly conducted in rodents. However, the availability of tailored neurotechnologies, for experiments conducted in small animals, is limited mostly due to size constraints. Moreover, when developing implantable devices that would target the spinal cord, careful selection of the materials used is equally important. However, understanding the underlying mechanism leading to a specific behaviour or motor outputs requires exploring and quantifying new methods of stimulation. For instance, optogenetics has been gaining a lot of popularity in the field of neural stimulation as it is a more specific technique that could help neuroscientists map the neuronal circuitry within the human body. Thus, apart from developing spinal cord implants that resemble best the anatomy of the body, while inducing as little stress as possible on the spinal cord, for exploratory reasons the developed implants must provide optogenetic compatibility. Therefore, this thesis reports the development as well as the characterization of both passive and active spinal cord implants with optogenetic compatibility.
To achieve the desired goal of having a fully implantable, flexible spinal cord implant with optogenetic compatibility, a scalable and reproducible microfabrication process has been developed. Materials such as graphene, for transparency, flexibility and conductivity were used to develop the microelectrode arrays. Moreover, soft, polymeric encapsulation was employed to sustain the high flexibility and transparency of the implant. The end result of the microfabrication process would lead to a device consisting of a multi-layered graphene structure between two polymeric-based encapsulation layers and metal test pads for interconnection to the outside world. However, towards achieving this final structure, several challenges were encountered. Suspension of the implants after developing them on a rigid substrate, yet ensuring high quality for the graphene layer leads to several iterations of the fabrication process. Despite the challenges encountered, several prototypes were successfully developed. However, having prototypes that can only validate the process flow would not suffice. Therefore, extensive evaluation of the devices has been conducted and reported. Methods such as Raman spectroscopy and optical transmittance to evaluate the graphene layer or cyclic voltammetry and electrochemical impedance spectroscopy to characterize the performance of the fabricated devices were employed. The degree of transparency obtained using the reported microfabrication process was ~78 %, leading to the conclusion that the number of graphene layers for the final device was 10. It has been proven that graphene does not deteriorate over time when soaked in saline solution for several consecutive days and apart from that, the graphene-based implants showed no performance deterioration when bent over rods down to 3 mm in diameter. Moreover, the graphene electrodes provided impedance values of ~8 kΩ at 1 kHz frequencies, values comparable to what literature has previously reported. Apart from developing a passive graphene-based spinal cord implant, the focus of this thesis was also to fabricate and characterize an active implant. However, embedding active components with a flexible, graphene-based array of electrodes is not trivial. Therefore, system integration of small test chips was investigated and after several iterations of flip-chip bonding processes, a complete, active, graphene-based prototype was obtained. The measurements performed after the bonding process have proven that both bonding on graphene-only as well as on graphene and metal substrates is possible and the four-point measurement results indicated resistance values ranging from 10 mΩ up to 16 Ω for individual connections, depending on the substrate used.
Therefore, with this research project, not only the first fully transparent, graphene-based spinal cord implants have been developed but also the results obtained from their characterization illustrate that the process is stable and the performance of the devices is promising.

Neural interface in the form of microelectrodes is used to monitor and treat spinal cord injury and other neurological disorders by the means of recording and stimulation. Despite the apparent result of these electrical interventions, understanding of the mechanism behind neural stimulation is still inadequate. The use of optical monitoring during implantation is limited due to the use of opaque electrode partially blocking the implantation site. While the use of transparent conductor for an electrode is not uncommon in general electronics where indium tin oxide (ITO) is widely used for displays, however ITO is not suitable for implantation due to its brittle nature[1]. An alternative material to fabricate transparent electrodes is graphene, a single layer of carbon atom forming sp2 hybridization. Its high charge mobility, flexibility, mechanical strength, and optical transparency make it suitable for various flexible electronics applications including implantable microelectrode arrays. In biomedical fields, graphene has shown potential application as biosensor, stimulation and recording electrode[2]. Although fabrication of graphene microelectrodes has been previously shown[3], graphene had to be transferred manually for each layer. The high temperature needed during graphene deposition makes device fabrication directly on the flexible material impossible. Instead, the fabrication process relies on a transferring process of graphene layer from a growing medium with a high thermal budget to another desired substrate. The manual transfer process of graphene is a skill-dependant process with low scalability. In this work, a method of fabricating encapsulated graphene electrodes in polydimethylsiloxane (PDMS) with a controlled wafer-scale graphene transfer is proposed. Graphene transfer is done by wafer-assisted PDMS-PDMS bonding. The novel use of PDMS as an encapsulation material for graphene electrode is due to its biocompatibility, flexibility and optical transmittance. The transferred graphene was patterned on the PDMS by using oxygen plasma. Holes with a diameter of 10 μm was able to be patterned while maintaining the conductivity of the graphene layer. A combination of titanium and aluminium was used as metal contacts, the titanium provides a good contact resistance to graphene layer while aluminium allows wire bonding process to be performed on the contacts. Difference in material characteristics, such as the thermal expansion coefficient has become one of the challenges during the fabrication process. Despite these challenges, the fabrication process for the electrode array was designed and tested. Conductivity of the patterned graphene layer was tested. The optical transmittance measurement showed up to 77% transmittance was achieved on the graphene encapsulated by PDMS.

Neurostimulators have been developed over the past few decades to treat various diseases, such as Parkinson’s disease, chronic pain, epilepsy, migraine and bladder dysfunction. One of the major design challenges is the selection of a powering method that could supply mW power levels to miniaturized implanted devices. Among several methods, wireless power transfer is often used to directly supply the electronics or to recharge an implanted battery. In particular, the interest in ultrasonic waves as source of power and data for implantable medical devices has recently grown, particularly due to the advantages over RF and inductive coupling power transfer. In fact, ultrasounds can deliver higher power to mm-sized and deeply (> 10 cm) implanted receivers than the other techniques. Moreover, acoustic waves do not interfere with electromagnetic fields.Conventionally, biphasic constant current or constant voltage pulses are selected for stimulating nerve tissue. The first (usually cathodic) phase has the purpose of activating the excitable nerve fibres, while the second (usually anodic) phase reverses the direction of the stimulation current to avoid long-term accumulation of charge. Alternatively, Ultra-High-Frequency stimulation can be employed. This consists of current or voltage pulses at a high frequency (≥ 1 MHz), which are obtained from a DC source and the operation of high-frequency switches. In both techniques, when a wireless supply is chosen, the received AC signal is rectified, stored and regulated to operate the usually low-voltage blocks of the rest of the system. Nonetheless, up-conversion of the signal is often required to provide enough voltage compliance to operate an output stage connected to the stimulating electrodes.Taking a more radical approach, it is possible to avoid the lossy conversion from AC to regulated DC and from that to high-frequency stimulation by eliminating the need of power storage, regulation and up-conversion. To this end, the aim of this work was to design a circuit topology that generates ultra-high-frequency pulses by rectifying the sinusoid obtained from an ultrasound transducer and using the obtained waveform to directly stimulate the tissue in a biphasic fashion. This could result in a highly efficient and miniature circuit, which has the potential to be used for stimulating small peripheral nerves. Simulations in LTSpice were conducted to analyse the performance of the proposed system. The operation was then verified by measurements with a fabricated prototype, which was capable of providing biphasic pulses by receiving a signal from ultrasound piezoelectric transducers and driving a pair of electrodes.