Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> A. Equivalent Circuit Analysis of the Probe/Tissue Interface <s> A method is described for the manufacture of a three-dimensional electrode array geometry for chronic intracortical stimulation. This silicon based array consists of a 4.2*4.2*0.12 mm thick monocrystalline substrate, from which project 100 conductive, silicon needles sharpened to facilitate cortical penetration. Each needle is electrically isolated from the other needles, and is about 0.09 mm thick at its base and 1.5 mm long. The sharpened end of each needle is coated with platinum to facilitate charge transfer into neural tissue. The following manufacturing processes were used to create this array: thermomigration of 100 aluminum pads through an n-type silicon block, creating trails of highly conductive p/sup +/ silicon isolated from each other by opposing pn junctions; a combination of mechanical and chemical micromachining which creates individual penetrating needles of the p/sup +/ silicon trails; metal deposition to create active electrode areas and electrical contact pads; and array encapsulation with polyimide. > <s> BIB001 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> A. Equivalent Circuit Analysis of the Probe/Tissue Interface <s> Silicon-based microsystems are being developed to interface with the central nervous system (CNS) at the cellular level. Dense three-dimensional (3-D) microelectrode arrays with as many as several hundred sites permit acute and semichronic single-unit recording and stimulation, while on-chip circuitry for site selection, amplification, and multiplexing reduces noise and limits the number of output leads to manageable levels. Hybrid implant-mounted circuitry can be used to separate single units from baseline noise and provide simultaneous wireless access to more than a hundred information channels. This article focuses on the technology for electronically interfacing with the CNS at the cellular level. Devices based on silicon-on-insulator technology and silicon array structures not based as directly on the planar processes of ICs are given notice. Tissue interface and cabling problems still exist for long-term applications but the basic technology platform is robust and should allow engineering solutions to be developed over time. Present technology is consistent with real breakthroughs in our understanding of the brain at the circuit/system level during the coming decade though detailed mapping that has been impossible in the past. Such mapping could also serve as a basis for prosthetic devices for treating some of mankind's most debilitating disorders. <s> BIB002 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> A. Equivalent Circuit Analysis of the Probe/Tissue Interface <s> Microelectrode arrays and microprobes have been widely utilized to measure neuronal activity, both in vitro and in vivo. The key advantage is the capability to record and stimulate neurons at multiple sites simultaneously. However, unlike the single-cell or single-channel resolution of intracellular recording, microelectrodes detect signals from all possible sources around the sensor. Here, we review the current understanding of microelectrode signals and the techniques for analyzing them. We introduce the ongoing advancements in microelectrode technology, with focus on achieving higher resolution and quality of recordings by means of monolithic integration with on-chip circuitry. We show how recent advanced microelectrode array measurement methods facilitate the understanding of single neurons as well as network function. <s> BIB003 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> A. Equivalent Circuit Analysis of the Probe/Tissue Interface <s> To ensure long-term consistent neural recordings, next-generation intracortical microelectrodes are being developed with an increased emphasis on reducing the neuro-inflammatory response. The increased emphasis stems from the improved understanding of the multifaceted role that inflammation may play in disrupting both biologic and abiologic components of the overall neural interface circuit. To combat neuro-inflammation and improve recording quality, the field is actively progressing from traditional inorganic materials towards approaches that either minimizes the microelectrode footprint or that incorporate compliant materials, bioactive molecules, conducting polymers or nanomaterials. However, the immune-privileged cortical tissue introduces an added complexity compared to other biomedical applications that remains to be fully understood. This review provides a comprehensive reflection on the current understanding of the key failure modes that may impact intracortical microelectrode performance. In addition, a detailed overview of the current status of various materials-based approaches that have gained interest for neural interfacing applications is presented, and key challenges that remain to be overcome are discussed. Finally, we present our vision on the future directions of materials-based treatments to improve intracortical microelectrodes for neural interfacing. <s> BIB004 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> A. Equivalent Circuit Analysis of the Probe/Tissue Interface <s> The application of microfabrication to the development of biomedical implants has produced a new generation of miniaturized technology for assisting treatment and research. Microfabricated implantable devices (μID) are an increasingly important tool, and the development of new μIDs is a rapidly growing field that requires new microtechnologies able to safely and accurately function in vivo. Here, we present a review of μID research that examines the critical role of material choice in design and fabrication. Materials commonly used for μID production are identified and presented along with their relevant physical properties and a survey of the state-of-the-art in μID development. The consequence of material choice as it pertains to microfabrication and biocompatibility is discussed in detail with a particular focus on the divide between hard, rigid materials and soft, pliable polymers. <s> BIB005 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> A. Equivalent Circuit Analysis of the Probe/Tissue Interface <s> Computations in brain circuits involve the coordinated activation of large populations of neurons distributed across brain areas. However, monitoring neuronal activity in the brain of intact animals with high temporal and spatial resolution has remained a technological challenge. Here we address this challenge by developing dense, three-dimensional (3-D) electrode arrays for electrophysiology. The 3-D arrays constitute the front-end of a modular and configurable system architecture that enables monitoring neuronal activity with unprecedented scale and resolution. <s> BIB006 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> A. Equivalent Circuit Analysis of the Probe/Tissue Interface <s> New silicon probes known as Neuropixels are shown to record from hundreds of neurons simultaneously in awake and freely moving rodents. <s> BIB007 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> A. Equivalent Circuit Analysis of the Probe/Tissue Interface <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> BIB008 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> A. Equivalent Circuit Analysis of the Probe/Tissue Interface <s> Investigation and modulation of neural circuits in vivo at the cellular level are very important for studying functional connectivity in a brain. Recently, neural probes with stimulation capabilities have been introduced, and they provided an opportunity for studying neural activities at a specific region in the brain using various stimuli. However, previous methods have a limitation in dissecting long-range neural circuits due to inherent limitations on their designs. Moreover, the large size of the previously reported probes induces more significant tissue damage. Herein, we present a multifunctional multi-shank MEMS neural probe that is monolithically integrated with an optical waveguide for optical stimulation, microfluidic channels for drug delivery, and microelectrode arrays for recording neural signals from different regions at the cellular level. In this work, we successfully demonstrated the functionality of our probe by confirming and modulating the functional connectivity between the hippocampal CA3 and CA1 regions in vivo. Microelectromechanical neural probes can cause tissue damage and often cannot record from distant brain areas. Here the authors combine electrical recording, optical stimulation and microfluidic drug delivery in one multi-shank probe with thinner shanks to reduce damage and a flexible design to target long-range neural circuits. <s> BIB009
Neural recordings using implanted devices can detect a change in the extracellular field because of ion fluxes in the nearby condition, which permits recording of the small population activity as LFPs (<∼350 Hz), and, in certain situations, the spiking action or action potentials of single-neuron (∼kHz). The impedance is defined as the resistance to the current that flows between the implanted probe and interface of the tissue. The impedance estimates the capacity to record the pathological and physiological neural sign or for neural stimulation. By making use of the equivalent circuit model illustrated in Fig. 3(a) , the probe/tissue effective impedance can often be modelled, understood, and optimized. Here, V e is the signalling in the neuron and accepted as a low-impedance voltage source. R spread (or, R media ) indicates the impedance of the extracellular space and is dictated by the implanted device geometry. Besides, R e is the leakage resistance of the electrode and C e characterizes the capacitance of the probe/tissue interface. Finally, R s defines the resistance that exists in case of higher-level hardware, for example amplifiers. The magnitude of R s can be negligible or significant depending on the interconnection used to record/transmit signals BIB003 , BIB004 . In general, a lower impedance probe/tissue interface is desired and permits us to "see" the neural signal (Ve) more promptly. Like recording, implantable neural device stimulation is strengthened with a low probe/tissue interface resistance as well and results in a significant charge injection. Hence, having a low impedance interface is crucial in µm-scale electrodes for neural recording/stimulation. As both recording and stimulation circuits are identical to Fig. 3(a) , a ms-scale biphasic current stimulation introduces a momentary voltage incorporating rapid step, because of R spread , and initiates a capacitive charging due to C e  . Consequently, a small value of C e facilitates the significant potential drops at the neural interface. This may introduce electrolysis of water, degradation of electrode, as well as tissue damage. Recent advancement in the microelectronics manufacturing promoted the development of patterned, micromachined, and rigid probes BIB005 . Nowadays, the state-of-the-art devices like Michigan-style probes  and Utah arrays BIB002 are commercially available and has been utilized in neuroscience research. Furthermore, emerging Silicon-based implantable probe technologies such as Neuropixels for high-density neural recordings BIB007 , multifunctional probe BIB009 , as well as 3D probe for recording of coordinated brain activity from large population of neurons BIB006 have enriched us with new insights to study the brain. Regardless of numerous triumphs and creative revelations in neuroscience (from the disclosure of spot and framework cells to mapping and motor cortex stimulation), still implantable neural devices face numerous limitations that circumscribe their chronic implementation. Owing to the rigid nature of the implanted devices, it frequently prompts insulation failure and limits the recording/stimulating ability BIB001 . Accordingly, recording quality, stimulation limit, and life expectancy of an implantable neural device can be condensed down to its capacity to oppose or defeat increments in electrical impedance. Due to the surgical procedure of the implantable neural device, it presents both intense (acute) and constant (chronic) tissue damage, notwithstanding, there are more spotlights on the probe/tissue biointegration and lifetime instead of the impact on neurological function BIB008 . In the following subsections some of the critical aspects of the implant/tissue biointegration will be addressed in terms of electrical viewpoint along with the approaches to alleviate these issues.