Technologies that are employed to record and modulate neural activities are rapidly advancing. This advancement could bring breakthroughs in our understanding of brain function and enable scientists to diagnose and treat neural diseases and disorders. Combining multiple modalities to study brain function, from single cells to large networks, offers insights beyond those offered by a single-modal platform using only electrical recording or modulation. However, the tools to enable such studies are yet to be developed and still face significant challenges that remain to be resolved to allow multimodal measurement without any of the modalities interfering with one another.
Recently, graphene-based neural electrodes have shown great promise for combining optical and electrical modalities in a single device. However, their complicated fabrication process, high impedance, and low charge storage capacity currently limit their application. In addition, their compatibility with the magnetic domain remains to be proven.
In this thesis, graphene-based microfabricated platform technology is introduced for the manufacturing of multimodal neural interfaces. First, a transfer-free fabrication process is demonstrated to fabricate multilayer graphene electrodes on parylene-C substrates. Full electrochemical characterization is performed on these graphene electrodes and a comparison is made with conventional metal-based electrodes. Second, a nanoparticle printing technique, spark ablation, is leveraged to print platinumnanoparticles on the graphene electrode surface to enhance its electrochemical characteristics even further without compromising its optical transparency. Third, a hybrid encapsulation stack is fabricated and validated that includes parylene C and PDMS with thin ceramic interlayers to be employed as the encapsulation layer on the final neural-interface device.
The multimodal platform technology introduced in this thesis can be used as a tool inmultimodal measurements combining electrical, optical, and magnetic domains. The fabricated multilayer graphene electrodes showthe highest charge storage capacity among all CVD graphene electrodes to date. They show no optical and MRI artifacts. Moreover, the fabricated electrodes and encapsulation stack both reveal the high optical transparency required for optical measurements. Local platinum nanoparticle printing can improve the impedance, charge storage, and charge injection capacity by 4.5, 15, and 3.6 times, respectively.@en

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

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. [Figure not available: see fulltext.].

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In this paper, we investigate the long-term adhesion strength and barrier property of our recently proposed encapsulation stack that includes PDMS-Parylene C and PECVD interlayers (SiO2 and SiC) for adhesion improvement. To evaluate the adhesion strength of our proposed stack, the sample preparation consisted in depositing approximately 25 nm of SiC and 25 nm of SiO2 on half wafers, previously coated with Parylene C. Next, $50 \mu \mathrm{m}$ PDMS was spin-coated on top. Finally, the samples were detached from the Si wafer and soaked in a PBS solution at 67°C to accelerate the aging process. Two samples were also implanted, subcutaneously, on the left and right subscapular regions of a rat. The optical inspection and peel tests performed after two months confirmed our preliminary findings and showed a significant improvement of the adhesion in our proposed encapsulation stack compared to the case of PDMS on Parylene C alone. In addition, the X-ray photoelectron spectroscopy(XPS) analysis at the interface between SiC and Parylene C showed different peaks for the interface compared to the reference spectra, which could be an indication of a chemical bond. Finally, water vapor transmission rate (WVTR) tests were performed to investigate the barrier property of our proposed encapsulation stack against water vapor transmission. The results demonstrated that the proposed stack acts as a significantly (two orders of magnitude) higher barrier against moisture compared to only Parylene C and PDMS encapsulation layers. The proposed method yields a fully transparent encapsulation stack over a broad wavelength spectrum that can be used for the conformal encapsulation of flexible devices and thus, making them compatible with techniques such as optical imaging and optogenetics.@en

Our limited understanding of the nervous system forms a bottleneck which impedes the effective treatment of neurological disorders. In order to improve patient outcomes it is highly desirable to interact with the nervous tissue at the resolution of individual cells. As neurons number in the billions and transmit signals electrically, high-density, cellular-resolution microelectrode arrays will be a useful tool for both treatment and research.This paper investigates the advantages and versatility of laser-patterning technologies for the development of such high-density microelectrode arrays in flexible polymer substrates. In particular, it aims to elucidate the mechanisms involved in laser patterning of thin polymers on top of thin metal layers. For this comparative study, a pulsed picosecond laser (Schmoll Picodrill) with two separate wavelengths (1064 nm (infrared (IR)) and 355 nm (ultraviolet (UV))) was used. A 5 $\mu$ m thick electroplated layer of gold (Au) was used to form the microelectrodes. Laser-patterning was investigated to expose the Au electrodes when encapsulated by two different thermoplastic polymers: thermoplastic polyurethane (TPU), and Parylene-C, with thicknesses of maximum 25 $\mu$ m. The electrode diameter and the distance between electrodes were reduced down to 35 $\mu$ m and 30 $\mu$ m, respectively. The structures were evaluated using optical microscopy and white light interferometry and the results indicated that both laser wavelengths can be successfully used to create high-density microelectrode arrays in polymer substrates. However, due to the lower absorption coefficient of metals in the IR spectrum, a higher uniformity of the exposed Au layer was observed when IR-based lasers were used. This paper provides more insight into the mechanisms involved in laser-patterning of thin film polymers and demonstrates that it can be a reliable and cost-effective method for the rapid prototyping of thin-film neural interfaces.@en

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.

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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 plasmatreated parylene. We aim to use the proposed solution to package bare silicon chips on active implants. @en

Active implantable medical devices have been developed for diagnosis, monitoring and treatment of large variety of neural disorders. Since the mechanical properties of these devices need to be matched to the tissue, soft materials, such as polymers are often preferred as a substrate [1]. Parylene is a good candidate, as it is highly biocompatible and it can be deposited/etched using standard Integrated Circuit (IC) fabrication methods/processes. Further, the implantable devices should be smart, a goal that can be accomplished by including ICs. These ICs, often come in the form of additional pre-packaged components that are assembled on the implant in a heterogenous process. Such a hybrid integration, however, does not allow for size minimization, which is so critical in these applications, as otherwise the implants can cause severe damage to the tissue. On the other hand, it is essential that all components are properly packaged to prevent early failure due to moisture penetration [2].
In this work we use a previously developed semi-flexible platform technology based on a Parylene substrate and Pt metallization, which allows integration of electronic components with a flexible substrate in a monolithic process. We use an IC fabrication-based platform that allows for the fabrication of several rigid regions including Application-Specific Integrated Circuits (ASICs) and other components connected to each other by means of flexible interconnects. We aim to add more functionality to this technology and thereby extend it to a platform for a variety of medical applications. An example of such functionality is integrating Light Emitting Diodes (LEDs) for optogenetic stimulation or integrating Capacitive Micromachined Ultrasound Transducers (CMUTs) for ultrasound stimulation or ultrasound wireless power transfer. Since the long-term reliability is critical for implantable devices, we intend to reinforce our implant with an extra Polydimethylsiloxane (PDMS) encapsulation layer that relies on the low viscosity of the uncured rubber to flow in every detail of the surface to prevent void formation [3]. Therefore, this work also focuses on enhancing the adhesion of PDMS to Parylene, as it must remain strong for the required lifetime of the device.@en