Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> B. Interruption in Probe/Tissue Circuit Due to Implantation Failures <s> Advanced fabrication techniques have now made it possible to produce microelectrode arrays for recording the electrical activity of a large number of neurons in the intact brain for both clinical and basic science applications. However, the long-term recording performance desired for these applications is hindered by a number of factors that lead to device failure or a poor signal-to-noise ratio (SNR). The goal of this study was to identify factors that can affect recording quality using theoretical analysis of intracortical microelectrode recordings of single-unit activity. Extracellular microelectrode recordings were simulated with a detailed multi-compartment cable model of a pyramidal neuron coupled to a finite-element volume conductor head model containing an implanted recording microelectrode. Recording noise sources were also incorporated into the overall modeling infrastructure. The analyses of this study would be very difficult to perform experimentally; however, our model-based approach enabled a systematic investigation of the effects of a large number of variables on recording quality. Our results demonstrate that recording amplitude and noise are relatively independent of microelectrode size, but instead are primarily affected by the selected recording bandwidth, impedance of the electrode–tissue interface and the density and firing rates of neurons surrounding the recording electrode. This study provides the theoretical groundwork that allows for the design of the microelectrode and recording electronics such that the SNR is maximized. Such advances could help enable the long-term functionality required for chronic neural recording applications. <s> BIB001 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> B. Interruption in Probe/Tissue Circuit Due to Implantation Failures <s> Neural prostheses have already a long history and yet the cochlear implant remains the only success story about a longterm sensory function restoration. On the other hand, neural implants for deep brain stimulation are gaining acceptance for variety of disorders including Parkinson’s disease and obsessive-compulsive disorder. It is anticipated that the progress in the field has been hampered by a combination of technological and biological factors, such as the limited understanding of the longterm behaviour of implants, unreliability of devices, biocompatibility of the implants among others. While the field's understanding of the cell biology of interactions at the biotic-abiotic interface has improved, relatively little attention has been paid on the mechanical factors (stress, strain), and hence on the geometry that can modulate it. This focused review summarizes the recent progress in the understanding of the mechanisms of mechanical interaction between the implants and the brain. The review will give an overview of the factors by which the implants interact acutely and chronically with the tissue: blood-brain barrier breach, vascular damage, micromotions, diffusion etc. We propose some design constraints to be considered in future studies. Aspects of the chronic cell-implant interaction will be discussed in view of the chronic local inflammation and the ways of modulating it. <s> BIB002 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> B. Interruption in Probe/Tissue Circuit Due to Implantation Failures <s> Abstract Neurotechnology is facing an exponential growth in the recent decades. Neural electrode-tissue interface research has been well recognized as an instrumental component of neurotechnology development. While satisfactory performance was demonstrated in some applications, such as cochlear implants and deep brain stimulators, more advanced devices requiring higher resolution for recording or microstimulation still face significant challenges in reliability and longevity. We review the most recent findings that shed light on the sources of poor reliability and longevity in neural electrodes, including the material failure, biological tissue response and the interplay between the two. We introduce newly developed characterization tools from electrophysiology models, molecular and biochemical analysis, material characterization to live imaging. Effective strategies for improving the interface are also highlighted. Finally, we discuss the challenges and opportunities in improving the interface and achieving seamless integration between the implanted electrodes and neural tissue both anatomically and functionally. <s> BIB003 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> B. Interruption in Probe/Tissue Circuit Due to Implantation Failures <s> Understanding the dynamics and architecture of the nervous system requires tools for recording and modulating the activity of billions of neurons. This Review explores the history of neural engineering and the materials innovation at the interface between neural tissue and synthetic sensors. <s> BIB004 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> B. Interruption in Probe/Tissue Circuit Due to Implantation Failures <s> Bidirectional interfacing with the nervous system enables neuroscience research, diagnosis, and therapy. This two-way communication allows us to monitor the state of the brain and its composite networks and cells as well as to influence them to treat disease or repair/restore sensory or motor function. To provide the most stable and effective interface, the tools of the trade must bridge the soft, ion-rich, and evolving nature of neural tissue with the largely rigid, static realm of microelectronics and medical instruments that allow for readout, analysis, and/or control. In this Review, we describe how the understanding of neural signaling and material-tissue interactions has fueled the expansion of the available tool set. New probe architectures and materials, nanoparticles, dyes, and designer genetically encoded proteins push the limits of recording and stimulation lifetime, localization, and specificity, blurring the boundary between living tissue and engineered tools. Understanding these approaches, their modality, and the role of cross-disciplinary development will support new neurotherapies and prostheses and provide neuroscientists and neurologists with unprecedented access to the brain. <s> BIB005 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> B. Interruption in Probe/Tissue Circuit Due to Implantation Failures <s> Neurophysiology is the branch of physiology concerned with understanding the function of neural systems. Neural engineering (also known as neuroengineering) is a discipline within biomedical engineering that uses engineering techniques to understand, repair, replace, enhance, or otherwise exploit the properties and functions of neural systems. In most cases neural engineering involves the development of an interface between electronic devices and living neural tissue. This review describes the origins of neural engineering, the explosive development of methods and devices commencing in the late 1950s, and the present-day devices that have resulted. The barriers to interfacing electronic devices with living neural tissues are many and varied, and consequently there have been numerous stops and starts along the way. Representative examples are discussed. None of this could have happened without a basic understanding of the relevant neurophysiology. I also consider examples of how neural engineering is repaying the debt to basic neurophysiology with new knowledge and insight. <s> BIB006 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> B. Interruption in Probe/Tissue Circuit Due to Implantation Failures <s> BACKGROUND ::: Dielectric damage occurring in vivo to neural electrodes, leading to conductive material exposure and impedance reduction over time, limits the functional lifetime and clinical viability of neuroprosthetics. We used silicon micromachined Utah Electrode Arrays (UEAs) with iridium oxide (IrOx) tip metallization and parylene C dielectric encapsulation to understand the factors affecting device resilience and drive improvements. ::: ::: ::: NEW METHOD ::: In vitro impedance measurements and finite element analyses were conducted to evaluate how exposed surface area of silicon and IrOx affect UEA properties. Through an aggressive in vitro reactive accelerated aging (RAA) protocol, in vivo parylene degradation was simulated on UEAs to explore agreement with our models. Electrochemical properties of silicon and other common electrode materials were compared to help inform material choice in future neural electrode designs. ::: ::: ::: RESULTS ::: Exposure of silicon on UEAs was found to primarily affect impedance at frequencies >1kHz, while characteristics at 1 kHz and below were largely unchanged. Post-RAA impedance reduction of UEAs was mitigated in cases where dielectric damage was more likely to expose silicon instead of IrOx. Silicon was found to have a per-area electrochemical impedance >10×higher than many common electrode materials regardless of doping level and resistivity, making it best suited for use as a low-shunting conductor. ::: ::: ::: COMPARISON WITH EXISTING METHODS ::: Non-semiconductor electrode materials commonly used in neural electrode design are more susceptible to shunting neural interface signals through dielectric defects, compared to highly doped silicon. ::: ::: ::: CONCLUSION ::: Strategic use of silicon and similar materials may increase neural electrode robustness against encapsulation failures. <s> BIB007
Poor encapsulation, material defects, and/or potentially unintended mechanical stresses causes cracking and delamination of the device BIB002 . Encapsulation failure, which occurs in between a week or a month after implantation, may expose the metallic interconnects. Insulation damage introduces additional resistive and capacitive pathways for current to flow (R d and C d in Fig. 3(b) ). This results in a false neural signal (or, noise) V NT from undesired cells BIB003 , BIB004 . In addition, the amplitude of the neural recording is diminished due to the low impedance shunting pathways of the neighbourhood condition. Likewise, these equivalent shunt pathways may divert current and stimulate non-target cells, decreasing stimulation ability. Corrosion due to chemical deterioration of the material used in the electrode presents a twofold negative impact. First, it destroys the conductive properties of the metallic interconnects (thus, expanding R s as well as diminishing C e ) and secondly, accommodating brain with harmful toxic ingredients, subsequently, expanding the immune response or causes cell death BIB005 . Careful materials choice and/or synthesis are vital in realizing a chemically stable and properly insulated implantable neural electrode. Though acute tissue damage because of the implanted neural probe in the brain could expeditiously recuperate, it is the long haul tissue response, and consequent inflammation at the implant site, that effectively adds to debasing the probe/tissue biointegration BIB006 , BIB007 . The neuroinflammatory reaction within the central nervous system of the brain is defined as the reaction of the immune system and is made from a blend of cellular and biochemical reactions, which detaches foreign components (for example, an implanted probe) from the tissue. During the acute stage, the surface of the implanted device attracts and activates microglia (central nervous system immune cell), which releases pro-inflammatory factors. Shortly thereafter, a thick astrocyte wraps the implanted neural device and the response advances to a chronic stage, where a scar (astrogliosis) is formed, as visualized in Fig. 3(c) . This chronic reaction, which is responsible for distancing the neuron from the implantation site can be caused by several factors BIB001 . In accordance with electrical interfacing, astrogliosis and the distancing of neurons near the implanted sites are in charge of (i) the introduction of additional impedance (Z scar ) and (ii) diminishing the amplitude of the neural recordings since living neurons are less and remotely away from the implant site ( Fig. 3(c) ). According to the both theory and experiments, the most extreme permissible separation between the probe and the cell membrane for a steady recording extends somewhere in the range of 50 and 100 µm BIB001 . An overview of the different failures upon the implantation of a probe into the intracortical tissue is illustrated in Fig. 4 .