Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Abstract It is believed that ramified resting microglial cells in the brain are differentiated from macrophage-like ameboid cells, although the mechanism for the differentiation is not fully understood. In the present study, we investigated whether the differentiation of microglial cells is observable in mixed brain cell culture prepared from newborn rat forebrains. In confluent mixed brain cell culture, both ramified and ameboid microglial cells were simultaneously present. The ramified cells were located in or under the astrocyte monolayer, while the ameboid cells were over the layer as revealed by confocal laser scan microscopy. The majority of ramified cells appeared after the astrocyte layer was completely formed and they downregulated the expression of the major histocompatibility complex antigen. Fibronectin was detected around ramified microglial cells, and laminin was also present in the astrocyte monolayer in mixed brain cell culture, while both proteins were not distributed near ameboid cells over the monolayer. When purified microglial cells were cultured on astrocyte-derived extracellular matrix in serum-free medium, they ramified. These results show that the differentiation of microglial cells is observable in culture and that astrocytes may play pivotal roles in the differentiation mainly by secreting insoluble factors. <s> BIB001 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> The promise of advanced neuroprosthetic systems to significantly improve the quality of life for a segment of the deaf, blind, or paralyzed population hinges on the development of an efficacious, and safe, multichannel neural interface for the central nervous system. The candidate implantable device that is to provide such an interface must exceed a host of exacting design parameters. The authors present a thin-film, polyimide-based, multichannel intracortical Bio-MEMS interface manufactured with standard planar photo-lithographic CMOS-compatible techniques on 4-in silicon wafers. The use of polyimide provides a mechanically flexible substrate which can be manipulated into unique three-dimensional designs. Polyimide also provides an ideal surface for the selective attachment of various important bioactive species onto the device in order to encourage favorable long-term reactions at the tissue-electrode interface. Structures have an integrated polyimide cable providing efficient contact points for a high-density connector. This report details in vivo and in vitro device characterization of the biological, electrical and mechanical properties of these arrays. Results suggest that these arrays could be a candidate device for long-term neural implants. <s> BIB002 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> There are four criteria that must be considered when choosing material for an implanted electrode: (1) tissue response, (2) allergic response, (3) electrode-tissue impedance, and (4) radiographic visibility. This paper discusses these four criteria and identifies the materials that are the best candidates for such electrodes. For electrodes that make ohmic contact with tissues: gold, platinum, platinum–iridium, tungsten, and tantalum are good candidates. The preferred insulating materials are polyimide and glass. The characteristics of stimulator output circuits and the importance of the bidirectional wave- form in relation to electrode decomposition are discussed. The paper concludes with an analysis, the design criteria, and the special properties and materials for capacitive recording and stimulating electrodes. © 2003 Biomedical Engineering Society. <s> BIB003 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> The ability to successfully interface the brain to external electrical systems is important both for fundamental understanding of our nervous system and for the development of neuroprosthetics. Silicon microelectrode arrays offer great promise in realizing this potential. However, when they are implanted into the brain, recording sensitivity is lost due to inflammation and astroglial scarring around the electrode. The inflammation and astroglial scar are thought to result from acute injury during electrode insertion as well as chronic injury caused by micromotion around the implanted electrode. To evaluate the validity of this assumption, the finite element method (FEM) was employed to analyze the strain fields around a single Michigan Si microelectrode due to simulated micromotion. Micromotion was mimicked by applying a force to the electrode, fixing the boundaries of the brain region and applying appropriate symmetry conditions to nodes lying on symmetry planes. Characteristics of the deformation fields around the electrode including maximum electrode displacement, strain fields and relative displacement between the electrode and the adjacent tissue were examined for varying degrees of physical coupling between the brain and the electrode. Our analysis demonstrates that when physical coupling between the electrode and the brain increases, the micromotion-induced strain of tissue around the electrode decreases as does the relative slip between the electrode and the brain. These results support the use of neuro-integrative coatings on electrode arrays as a means to reduce the micromotion-induced injury response. <s> BIB004 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Implanting electrical devices in the nervous system to treat neural diseases is becoming very common. The success of these brain-machine interfaces depends on the electrodes that come into contact with the neural tissue. Here we show that conventional tungsten and stainless steel wire electrodes can be coated with carbon nanotubes using electrochemical techniques under ambient conditions. The carbon nanotube coating enhanced both recording and electrical stimulation of neurons in culture, rats and monkeys by decreasing the electrode impedance and increasing charge transfer. Carbon nanotube-coated electrodes are expected to improve current electrophysiological techniques and to facilitate the development of long-lasting brain-machine interface devices. <s> BIB005 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> In neuroprosthetic applications, long-term electrode viability is necessary for robust recording of the activity of neural populations used for generating communication and control signals. The corrosion of tungsten microwire electrodes used for intracortical recording applications was analyzed in a controlled bench-top study and compared to the corrosion of tungsten microwires used in an in vivo study. Two electrolytes were investigated for the bench-top electrochemical analysis: 0.9% phosphate buffered saline (PBS) and 0.9% PBS containing 30 mM of hydrogen peroxide. The oxidation and reduction reactions responsible for corrosion were found by measurement of the open circuit potential and analysis of Pourbaix diagrams. Dissolution of tungsten to form the tungstic ion was found to be the corrosion mechanism. The corrosion rate was estimated from the polarization resistance, which was extrapolated from the electrochemical impedance spectroscopy data. The results show that tungsten microwires in an electrolyte of PBS have a corrosion rate of 300-700 μm/yr. The corrosion rate for tungsten microwires in an electrolyte containing PBS and 30 mM H₂O₂ is accelerated to 10,000-20,000 μm/yr. The corrosion rate was found to be controlled by the concentration of the reacting species in the cathodic reaction (e.g. O₂ and H₂O₂). The in vivo corrosion rate, averaged over the duration of implantation, was estimated to be 100 μm/yr. The reduced in vivo corrosion rate as compared to the bench-top rate is attributed to decreased rate of oxygen diffusion caused by the presence of a biological film and a reduced concentration of available oxygen in the brain. <s> BIB006 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Abstract The function and longevity of implantable microelectrodes for chronic neural stimulation depends heavily on the electrode materials, which need to present high charge injection capability and high stability. While conducting polymers have been coated on neural microelectrodes and shown promising properties for chronic stimulation, their practical applications have been limited due to unsatisfying stability. Here, poly(3,4-ethylenedioxythiophene) (PEDOT) doped with pure carbon nanotubes (CNTs) was electrochemically deposited on Pt microelectrodes to evaluate its properties for chronic stimulation. The PEDOT/CNT coated microelectrodes demonstrated much lower impedance than the bare Pt, and the PEDOT/CNT film exhibited excellent stability. For both acute and chronic stimulation tests, there is no significant increase in the impedance of the PEDOT/CNT coated microelectrodes, and none of the PEDOT/CNT films show any cracks or delamination, which have been the limitation for many conducting polymer coatings on neural electrodes. The charge injection limit of the Pt microelectrode was significantly increased to 2.5 mC/cm 2 with the PEDOT/CNT coating. Further in vitro experiments also showed that the PEDOT/CNT coatings are non-toxic and support the growth of neurons. It is expected that this highly stable PEDOT/CNT composite may serve as excellent new material for neural electrodes. <s> BIB007 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Implantable neural microelectrodes are critical to neuroscience research and emerging clinical applications including brain-controlled prostheses. A composite electrode consisting of a carbon fibre core, an insulating polymer coating and a polythiophene-based recording pad has now been developed that shows reduced chronic reactive tissue response in rats compared with existing architectures, owing to its smaller size and improved mechanical compliance with brain tissue. <s> BIB008 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Objective. Chronic neural recording in behaving animals is an essential method for studies of neural circuit function. However, stable recordings from small, densely packed neurons remains challenging, particularly over time-scales relevant for learning. Approach. We describe an assembly method for a 16-channel electrode array consisting of carbon fibers (<5??m diameter) individually insulated with Parylene-C and fire-sharpened. The diameter of the array is approximately 26??m along the full extent of the implant. Main results. Carbon fiber arrays were tested in HVC (used as a proper name), a song motor nucleus, of singing zebra finches where individual neurons discharge with temporally precise patterns. Previous reports of activity in this population of neurons have required the use of high impedance electrodes on movable microdrives. Here, the carbon fiber electrodes provided stable multi-unit recordings over time-scales of months. Spike-sorting indicated that the multi-unit signals were dominated by one, or a small number of cells. Stable firing patterns during singing confirmed the stability of these clusters over time-scales of months. In addition, from a total of 10 surgeries, 16 projection neurons were found. This cell type is characterized by sparse stereotyped firing patterns, providing unambiguous confirmation of single cell recordings. Significance. Carbon fiber electrode bundles may provide a scalable solution for long-term neural recordings of densely packed neurons. <s> BIB009 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Objective. Reliable chronic recordings from implanted neural probes remain a significant challenge; current silicon-based and microwire technologies experience a wide range of biotic and abiotic failure modes contributing to loss of signal quality. Approach. A multi-prong alternative strategy with potential to overcome these hurdles is introduced that combines a novel three dimensional (3D), polymer-based probe structure with coatings. Specifically, the Parylene C sheath-based neural probe is coated with neurotrophic and anti-inflammatory factors loaded onto a Matrigel carrier to encourage the ingrowth of neuronal processes for improved recording quality, reduce the immune response, and promote improved probe integration into brain tissue for reliable, long-term implementation compared to its rigid counterparts. Main results. The 3D sheath structure of the probe was formed by thermal molding of a surface micromachined Parylene C microchannel, with electrode sites lining the interior and exterior regions of the lumen. Electrochemical characterization of the probes via cyclic voltammetry and electrochemical impedance spectroscopy was performed and indicated suitable electrode properties for neural recordings (1?kHz electrical impedance of ?200 k? in vitro). A novel introducer tool for the insertion of the compliant polymer probe into neural tissue was developed and validated both in vitro using agarose gel and in vivo in the rat cerebral cortex. In vivo electrical functionality of the Parylene C-based 3D probes and their suitability for recording the neuronal activity over a 28-day period was demonstrated by maintaining the 1?kHz electrical impedance within a functional range (<400 k?) and achieving a reasonably high signal-to-noise ratio for detection of resolvable multi-unit neuronal activity on most recording sites in the probe. Immunohistochemical analysis of the implant site indicated strong correlations between the quality of recorded activity and the neuronal/astrocytic density around the probe. Significance. The provided electrophysiological and immunohistochemical data provide strong support to the viability of the developed probe technology. Furthermore, the obtained data provide insights into further optimization of the probe design, including tip geometry, use of neurotrophic and anti-inflammatory drugs in the Matrigel coating, and placement of the recording sites. <s> BIB010 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Numerous applications in neuroscience research and neural prosthetics, such as electrocorticogram (ECoG) recording and retinal prosthesis, involve electrical interactions with soft excitable tissues using a surface recording and/or stimulation approach. These applications require an interface that is capable of setting up high-throughput communications between the electrical circuit and the excitable tissue and that can dynamically conform to the shape of the soft tissue. Being a compliant material with mechanical impedance close to that of soft tissues, polydimethylsiloxane (PDMS) offers excellent potential as a substrate material for such neural interfaces. This paper describes an integrated technology for fabrication of PDMS-based stretchable microelectrode arrays (MEAs). Specifically, as an integral part of the fabrication process, a stretchable MEA is directly fabricated with a rigid substrate, such as a thin printed circuit board (PCB), through an innovative bonding technology-via-bonding-for integrated packaging. This integrated strategy overcomes the conventional challenge of high-density packaging for this type of stretchable electronics. Combined with a high-density interconnect technology developed previously, this stretchable MEA technology facilitates a high-resolution, high-density integrated system solution for neural and muscular surface interfacing. In this paper, this PDMS-based integrated stretchable MEA (isMEA) technology is demonstrated by an example design that packages a stretchable MEA with a small PCB. The resulting isMEA is assessed for its biocompatibility, surface conformability, electrode impedance spectrum, and capability to record muscle fiber activity when applied epimysially. <s> BIB011 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Microelectrode arrays for neural interface devices that are made of biocompatible thin-film polymer are expected to have extended functional lifetime because the flexible material may minimize adverse tissue response caused by micromotion. However, their flexibility prevents them from being accurately inserted into neural tissue. This article demonstrates a method to temporarily attach a flexible microelectrode probe to a rigid stiffener using biodissolvable polyethylene glycol (PEG) to facilitate precise, surgical insertion of the probe. A unique stiffener design allows for uniform distribution of the PEG adhesive along the length of the probe. Flip-chip bonding, a common tool used in microelectronics packaging, enables accurate and repeatable alignment and attachment of the probe to the stiffener. The probe and stiffener are surgically implanted together, then the PEG is allowed to dissolve so that the stiffener can be extracted leaving the probe in place. Finally, an in vitro test method is used to evaluate stiffener extraction in an agarose gel model of brain tissue. This approach to implantation has proven particularly advantageous for longer flexible probes (>3 mm). It also provides a feasible method to implant dual-sided flexible probes. To date, the technique has been used to obtain various in vivo recording data from the rat cortex. <s> BIB012 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Advances in techniques for recording large-scale brain activity contribute to both the elucidation of neurophysiological principles and the development of brain-machine interfaces (BMIs). Here we describe a neurophysiological paradigm for performing tethered and wireless large-scale recordings based on movable volumetric three-dimensional (3D) multielectrode implants. This approach allowed us to isolate up to 1,800 neurons (units) per animal and simultaneously record the extracellular activity of close to 500 cortical neurons, distributed across multiple cortical areas, in freely behaving rhesus monkeys. The method is expandable, in principle, to thousands of simultaneously recorded channels. It also allows increased recording longevity (5 consecutive years) and recording of a broad range of behaviors, such as social interactions, and BMI paradigms in freely moving primates. We propose that wireless large-scale recordings could have a profound impact on basic primate neurophysiology research while providing a framework for the development and testing of clinically relevant neuroprostheses. <s> BIB013 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Highly stretchable neural interface of concurrent robust electrical and mechanical properties is developed with a conducting polymer film as the sole conductor for both electrodes and leads. This neural interface offers benefits of conducting polymer electrodes in a demanding stretchable format, including low electrode impedance and high charge injection capacity, due to large electroactive surface area of the electrode. <s> BIB014 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Abstract Implantable neural electrodes must drastically improve chronic recording stability before they can be translated into long-term human clinical prosthetics. Previous studies suggest that sub-cellular sized and mechanically compliant probes may result in improved tissue integration and recording longevity. However, currently these design features are restricted by the opposing mechanical requirements needed for minimally damaging insertions. We designed a non-cytotoxic, carboxymethylcellulose (CMC) based dissolvable delivery vehicle (shuttle) to provide the mechanical support for insertion of ultra-small, ultra-compliant microfabricated neural probes. Stiff CMC-based shuttles rapidly soften immediately after being placed ∼1 mm above an open craniotomy as they absorb vapors from the brain. To address this, we developed a sophisticated targeting, high speed insertion (∼80 mm/s), and release system to implant these shuttles. After implantation, the goal is for the shuttle to dissolve away leaving only the electrodes behind. Here we show the histology of chronically implanted shuttles of large (300 μm × 125 μm) and small (100 μm × 125 μm) size at discrete time points over 12 weeks. Early time points show the CMC shuttle expanded after insertion as it absorbed moisture from the brain and slowly dissolved. At later time points neuronal cell bodies populate regions within the original shuttle tract. The large CMC shuttles show that the CMC expansion can cause extended secondary damage. On the other hand, the smaller CMC shuttles show limited secondary damage, wound closure by 4 weeks, absence of activated microglia at 12 weeks, as well as evidence suggesting neural regeneration at the implant site. This shuttle, therefore, shows great promise facilitating the implantation of nontraditional ultra-small, and ultra-compliant probes. <s> BIB015 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Traditional neuronal interfaces utilize metallic electrodes which in recent years have reached a plateau in terms of the ability to provide safe stimulation at high resolution or rather with high densities of microelectrodes with improved spatial selectivity. To achieve higher resolution it has become clear that reducing the size of electrodes is required to enable higher electrode counts from the implant device. The limitations of interfacing electrodes including low charge injection limits, mechanical mismatch and foreign body response can be addressed through the use of organic electrode coatings which typically provide a softer, more roughened surface to enable both improved charge transfer and lower mechanical mismatch with neural tissue. Coating electrodes with conductive polymers or carbon nanotubes offers a substantial increase in charge transfer area compared to conventional platinum electrodes. These organic conductors provide safe electrical stimulation of tissue while avoiding undesirable chemical reactions and cell damage. However, the mechanical properties of conductive polymers are not ideal, as they are quite brittle. Hydrogel polymers present a versatile coating option for electrodes as they can be chemically modified to provide a soft and conductive scaffold. However, the in vivo chronic inflammatory response of these conductive hydrogels remains unknown. A more recent approach proposes tissue engineering the electrode interface through the use of encapsulated neurons within hydrogel coatings. This approach may provide a method for activating tissue at the cellular scale, however several technological challenges must be addressed to demonstrate feasibility of this innovative idea. The review focuses on the various organic coatings which have been investigated to improve neural interface electrodes. <s> BIB016 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Calcium imaging is a versatile experimental approach capable of resolving single neurons with single-cell spatial resolution in the brain. Electrophysiological recordings provide high temporal, but limited spatial resolution, because of the geometrical inaccessibility of the brain. An approach that integrates the advantages of both techniques could provide new insights into functions of neural circuits. Here, we report a transparent, flexible neural electrode technology based on graphene, which enables simultaneous optical imaging and electrophysiological recording. We demonstrate that hippocampal slices can be imaged through transparent graphene electrodes by both confocal and two-photon microscopy without causing any light-induced artefacts in the electrical recordings. Graphene electrodes record high-frequency bursting activity and slow synaptic potentials that are hard to resolve by multicellular calcium imaging. This transparent electrode technology may pave the way for high spatio-temporal resolution electro-optic mapping of the dynamic neuronal activity. <s> BIB017 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Recent advances in nanotechnology have generated wide interest in applying nanomaterials for neural prostheses. An ideal neural interface should create seamless integration into the nervous system and performs reliably for long periods of time. As a result, many nanoscale materials not originally developed for neural interfaces become attractive candidates to detect neural signals and stimulate neurons. In this comprehensive review, an overview of state-of-the-art microelectrode technologies provided first, with focus on the material properties of these microdevices. The advancements in electro active nanomaterials are then reviewed, including conducting polymers, carbon nanotubes, graphene, silicon nanowires, and hybrid organic-inorganic nanomaterials, for neural recording, stimulation, and growth. Finally, technical and scientific challenges are discussed regarding biocompatibility, mechanical mismatch, and electrical properties faced by these nanomaterials for the development of long-lasting functional neural interfaces. <s> BIB018 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> On-demand, local delivery of drug molecules to target tissues provides a means for effective drug dosing while reducing the adverse effects of systemic drug delivery. This work explores an electrically controlled drug delivery nanocomposite composed of graphene oxide (GO) deposited inside a conducting polymer scaffold. The nanocomposite is loaded with an anti-inflammatory molecule, dexamethasone, and exhibits favorable electrical properties. In response to voltage stimulation, the nanocomposite releases drug with a linear release profile and a dosage that can be adjusted by altering the magnitude of stimulation. No drug passively diffuses from the composite in the absence of stimulation. In vitro cell culture experiments demonstrate that the released drug retains its bioactivity and that no toxic byproducts leach from the film during electrical stimulation. Decreasing the size and thickness of the GO nanosheets, by means of ultrasonication treatment prior to deposition into the nanocomposite, alters the f... <s> BIB019 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> With recent advancement in nanotechnology and materials science, we have been able to fabricate electronics on flexible, stretchable and 3D substrates to cover electrical functional units on soft and non-planar surfaces for monitoring, control and making smart systems. New requirements have been raised that electronics need to be implemented into objects with a minimal invasiveness followed by a 3D distribution of nano- and micro-scale sensor units in a large volume while maintaining mechanical ultra-flexibility. <s> BIB020 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> We describe recent advances in soft electronic interface technologies for neuroscience research. Here, low modulus materials and/or compliant mechanical structures enable modes of soft, conformal integration and minimally invasive operation that would be difficult or impossible to achieve using conventional approaches. We begin by summarizing progress in electrodes and associated electronics for signal amplification and multiplexed readout. Examples in large-area, surface conformal electrode arrays and flexible, multifunctional depth-penetrating probes illustrate the power of these concepts. A concluding section highlights areas of opportunity in the further development and application of these technologies. <s> BIB021 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> The development of microelectrodes capable of safely stimulating and recording neural activity is a critical step in the design of many prosthetic devices, brain–machine interfaces, and therapies for neurologic or nervous-system-mediated disorders. Metal electrodes are inadequate prospects for the miniaturization needed to attain neuronal-scale stimulation and recording because of their poor electrochemical properties, high stiffness, and propensity to fail due to bending fatigue. Here we demonstrate neural recording and stimulation using carbon nanotube (CNT) fiber electrodes. In vitro characterization shows that the tissue contact impedance of CNT fibers is remarkably lower than that of state-of-the-art metal electrodes, making them suitable for recording single-neuron activity without additional surface treatments. In vivo chronic studies in parkinsonian rodents show that CNT fiber microelectrodes stimulate neurons as effectively as metal electrodes with 10 times larger surface area, while eliciting a ... <s> BIB022 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Optogenetic studies of the peripheral nervous system and spinal cord are enabled by soft, wirelessly powered biocompatible devices. <s> BIB023 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Many chronic neuroscience studies require neural probes that can reliably record with a large number of electrodes in a densely configured array. Previous works have shown that adverse tissue reaction can be significantly reduced as probe shanks are scaled down toward subcellular dimensions. In addition, flexible probes can mitigate shear stress-induced tissue damage due to micromotion. However, both size reduction and flexibility compromise probe's ability to penetrate the pia mater, especially when many electrodes are distributed across multiple probe shanks. In this paper, we present a method to lithographically pattern a biodegradable silk coating that provides temporary mechanical stiffness for the surgical insertion of flexible probes without any conventional design constraints on the probe size, shape, or material. After insertion, the silk is completely dissolved in the tissue, only leaving the flexible minimum-geometry probes inside the brain. We validated the design by successfully inserting silk-backed 64-channel parylene probes into the motor cortex of Long-Evans rats (n = 6) and recorded in vivo neural activity for six weeks. <s> BIB024 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Neural recording and stimulation have great clinical potential. Long-term neural recording remains a challenge, however, as implantable electrodes eventually fail due to the adverse effects of the host tissue response to the indwelling implant. Astrocytes and microglia attempt to engulf the electrode, increasing the electrical impedance between the electrode and neurons, and possibly pushing neurons away from the recording site. Faster insertion speed, finer tip geometry, smaller size, and lower material stiffness all seem to decrease damage caused by insertion and reduce the intensity of the tissue response. However, electrodes that are too small result in buckling, making insertion impossible. In this paper, we assess the viability of high-speed (27.8 m/s) deployment of 25 μm, ferromagnetic microelectrodes into rat brain. To characterize functionality of magnetically inserted electrodes, 4 Long-Evans rats were implanted for 31 days with impedance measurements and neural recordings taken daily. Performance was compared to 150 μm diameter PlasticsOne electrodes since 25 μm electrodes buckled during "slow speed" insertion. Platinum-iron magnetically inserted electrodes resolved single unit activity throughout the duration of the study in one rat, and saw no significant change (p=0.970) in impedance (4.54% increase) from day 0 (Z0 ≈ 144 kΩ,Z31 ≈ 150 kΩ). These findings provide a proof-of-concept for magnetic insertion as a viable insertion method that enables nonbuckling implantation of small (25 μm) microelectrodes, with potential for neural recording applications. <s> BIB025 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <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> BIB026 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Neural-interfacing devices are an artificial mechanism for restoring or supplementing the function of the nervous system, lost as a result of injury or disease. Conducting polymers (CPs) are gaining significant attention due to their capacity to meet the performance criteria of a number of neuronal therapies including recording and stimulating neural activity, the regeneration of neural tissue and the delivery of bioactive molecules for mediating device-tissue interactions. CPs form a flexible platform technology that enables the development of tailored materials for a range of neuronal diagnostic and treatment therapies. In this review, the application of CPs for neural prostheses and other neural interfacing devices is discussed, with a specific focus on neural recording, neural stimulation, neural regeneration, and therapeutic drug delivery. <s> BIB027 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> In this technical report, Khodagholy and colleagues find that NeuroGrid, a planar, scalable and highly conformable electrode array, allows recordings of local-field potentials and stable single-unit activity from the surface of the rat cortex or hippocampus. The authors also validate NeuroGrid across species by showing that that it can capture LFP-modulated spiking activity intraoperatively in surgical patients, thus demonstrating its utility as tool for fundamental research on the human brain and in the clinic. <s> BIB028 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Implantable neuroprostheses are engineered systems designed to restore or substitute function for individuals with neurological deficits or disabilities. These systems involve at least one uni-or bidirectional interface between a living neural tissue and a synthetic structure, through which information in the form of electrons, ions or photons flows. Despite a few notable exceptions, the clinical dissemination of implantable neuroprostheses remains limited, because many implants display inconsistent long-term stability and performance, and are ultimately rejected by the body. Intensive research is currently being conducted to untangle the complex interplay of failure mechanisms. In this Review, we emphasize the importance of minimizing the physical and mechanical mismatch between neural tissues and implantable interfaces. We explore possible materials solutions to design and manufacture neurointegrated prostheses, and outline their immense therapeutic potential. <s> BIB029 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Objective: Subcellular-sized chronically implanted recording electrodes have demonstrated significant improvement in single unit (SU) yield over larger recording probes. Additional work expands on this initial success by combining the subcellular fiber-like lattice structures with the design space versatility of silicon microfabrication to further improve the signal-to-noise ratio, density of electrodes, and stability of recorded units over months to years. However, ultrasmall microelectrodes present very high impedance, which must be lowered for SU recordings. While poly(3,4-ethylenedioxythiophene) (PEDOT) doped with polystyrene sulfonate (PSS) coating have demonstrated great success in acute to early-chronic studies for lowering the electrode impedance, concern exists over long-term stability. Here, we demonstrate a new blend of PEDOT doped with carboxyl functionalized multiwalled carbon nanotubes (CNTs), which shows dramatic improvement over the traditional PEDOT/PSS formula. Methods: Lattice style subcellular electrode arrays were fabricated using previously established method. PEDOT was polymerized with carboxylic acid functionalized carbon nanotubes onto high-impedance (8.0 ± 0.1 MΩ: M ± S.E.) 250-μm2 gold recording sites. Results: PEDOT/CNT-coated subcellular electrodes demonstrated significant improvement in chronic spike recording stability over four months compared to PEDOT/PSS recording sites. Conclusion: These results demonstrate great promise for subcellular-sized recording and stimulation electrodes and long-term stability. Significance: This project uses leading-edge biomaterials to develop chronic neural probes that are small (subcellular) with excellent electrical properties for stable long-term recordings. High-density ultrasmall electrodes combined with advanced electrode surface modification are likely to make significant contributions to the development of long-term (permanent), high quality, and selective neural interfaces. <s> BIB030 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> In this review article, we focus on the various types of materials used in biomedical implantable devices, including the polymeric materials used as substrates and for the packaging of such devices. Polymeric materials are used because of the ease of fabrication, flexibility, and their biocompatible nature as well as their wide range of mechanical, electrical, chemical, and thermal behaviors when combined with different materials as composites. Biocompatible and biostable polymers are extensively used to package implanted devices, with the main criteria that include gas permeability and water permeability of the packaging polymer to protect the electronic circuit of the device from moisture and ions inside the human body. Polymeric materials must also have considerable tensile strength and should be able to contain the device over the envisioned lifetime of the implant. For substrates, structural properties and, at times, electrical properties would be of greater concern. Section 1 gives an introduction o... <s> BIB031 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Materials that can serve as long-lived barriers to biofluids are essential to the development of any type of chronic electronic implant. Devices such as cardiac pacemakers and cochlear implants use bulk metal or ceramic packages as hermetic enclosures for the electronics. Emerging classes of flexible, biointegrated electronic systems demand similar levels of isolation from biofluids but with thin, compliant films that can simultaneously serve as biointerfaces for sensing and/or actuation while in contact with the soft, curved, and moving surfaces of target organs. This paper introduces a solution to this materials challenge that combines (i) ultrathin, pristine layers of silicon dioxide (SiO2) thermally grown on device-grade silicon wafers, and (ii) processing schemes that allow integration of these materials onto flexible electronic platforms. Accelerated lifetime tests suggest robust barrier characteristics on timescales that approach 70 y, in layers that are sufficiently thin (less than 1 μm) to avoid significant compromises in mechanical flexibility or in electrical interface fidelity. Detailed studies of temperature- and thickness-dependent electrical and physical properties reveal the key characteristics. Molecular simulations highlight essential aspects of the chemistry that governs interactions between the SiO2 and surrounding water. Examples of use with passive and active components in high-performance flexible electronic devices suggest broad utility in advanced chronic implants. <s> BIB032 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <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> BIB033 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <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> BIB034 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Implanted brain electrodes construct the only means to electrically interface with individual neurons in vivo, but their recording efficacy and biocompatibility pose limitations on scientific and clinical applications. We showed that nanoelectronic thread (NET) electrodes with subcellular dimensions, ultraflexibility, and cellular surgical footprints form reliable, glial scar-free neural integration. We demonstrated that NET electrodes reliably detected and tracked individual units for months; their impedance, noise level, single-unit recording yield, and the signal amplitude remained stable during long-term implantation. In vivo two-photon imaging and postmortem histological analysis revealed seamless, subcellular integration of NET probes with the local cellular and vasculature networks, featuring fully recovered capillaries with an intact blood-brain barrier and complete absence of chronic neuronal degradation and glial scar. <s> BIB035 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Abstract Chronically implanted neural multi-electrode arrays (MEA) are an essential technology for recording electrical signals from neurons and/or modulating neural activity through stimulation. However, current MEAs, regardless of the type, elicit an inflammatory response that ultimately leads to device failure. Traditionally, rigid materials like tungsten and silicon have been employed to interface with the relatively soft neural tissue. The large stiffness mismatch is thought to exacerbate the inflammatory response. In order to minimize the disparity between the device and the brain, we fabricated novel ultrasoft electrodes consisting of elastomers and conducting polymers with mechanical properties much more similar to those of brain tissue than previous neural implants. In this study, these ultrasoft microelectrodes were inserted and released using a stainless steel shuttle with polyethyleneglycol (PEG) glue. The implanted microwires showed functionality in acute neural stimulation. When implanted for 1 or 8 weeks, the novel soft implants demonstrated significantly reduced inflammatory tissue response at week 8 compared to tungsten wires of similar dimension and surface chemistry. Furthermore, a higher degree of cell body distortion was found next to the tungsten implants compared to the polymer implants. Our results support the use of these novel ultrasoft electrodes for long term neural implants. Statement of Significance One critical challenge to the translation of neural recording/stimulation electrode technology to clinically viable devices for brain computer interface (BCI) or deep brain stimulation (DBS) applications is the chronic degradation of device performance due to the inflammatory tissue reaction. While many hypothesize that soft and flexible devices elicit reduced inflammatory tissue responses, there has yet to be a rigorous comparison between soft and stiff implants. We have developed an ultra-soft microelectrode with Young’s modulus lower than 1 MPa, closely mimicking the brain tissue modulus. Here, we present a rigorous histological comparison of this novel ultrasoft electrode and conventional stiff electrode with the same size, shape and surface chemistry, implanted in rat brains for 1-week and 8-weeks. Significant improvement was observed for ultrasoft electrodes, including inflammatory tissue reaction, electrode-tissue integration as well as mechanical disturbance to nearby neurons. A full spectrum of new techniques were developed in this study, from insertion shuttle to in situ sectioning of the microelectrode to automated cell shape analysis, all of which should contribute new methods to the field. Finally, we showed the electrical functionality of the ultrasoft electrode, demonstrating the potential of flexible neural implant devices for future research and clinical use. <s> BIB036 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Soft and conformable wearable electronics require stretchable semiconductors, but existing ones typically sacrifice charge transport mobility to achieve stretchability. We explore a concept based on the nanoconfinement of polymers to substantially improve the stretchability of polymer semiconductors, without affecting charge transport mobility. The increased polymer chain dynamics under nanoconfinement significantly reduces the modulus of the conjugated polymer and largely delays the onset of crack formation under strain. As a result, our fabricated semiconducting film can be stretched up to 100% strain without affecting mobility, retaining values comparable to that of amorphous silicon. The fully stretchable transistors exhibit high biaxial stretchability with minimal change in on current even when poked with a sharp object. We demonstrate a skinlike finger-wearable driver for a light-emitting diode. <s> BIB037 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Interfacing the nervous system with devices able to efficiently record or modulate the electrical activity of neuronal cells represents the underlying foundation of future theranostic applications in neurology and of current openings in neuroscience research. These devices, usually sensing cell activity via microelectrodes, should be characterized by safe working conditions in the biological milieu together with a well-controlled operation-life. The stable device/neuronal electrical coupling at the interface requires tight interactions between the electrode surface and the cell membrane. This neuro-electrode hybrid represents the hyphen between the soft nature of neural tissue, generating electrical signals via ion motions, and the rigid realm of microelectronics and medical devices, dealing with electrons in motion. Efficient integration of these entities is essential for monitoring, analyzing and controlling neuronal signaling but poses significant technological challenges. Improving the cell/electrode interaction and thus the interface performance requires novel engineering of (nano)materials: tuning at the nanoscale electrode's properties may lead to engineer interfacing probes that better camouflaged with their biological target. In this brief review, we highlight the most recent concepts in nanotechnologies and nanomaterials that might help reducing the mismatch between tissue and electrode, focusing on the device's mechanical properties and its biological integration with the tissue. <s> BIB038 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Intracranial electrodes are a vital component of implantable neurodevices, both for acute diagnostics and chronic treatment with open and closed-loop neuromodulation. Their performance is hampered by acute implantation trauma and chronic inflammation in response to implanted materials and mechanical mismatch between stiff synthetic electrodes and pulsating, natural soft host neural tissue. Flexible electronics based on thin polymer films patterned with microscale conductive features can help alleviate the mechanically induced trauma; however, this strategy alone does not mitigate inflammation at the device-tissue interface. In this study, we propose a biomimetic approach that integrates microscale extracellular matrix (ECM) coatings on microfabricated flexible subdural microelectrodes. Taking advantage of a high-throughput process employing micro-transfer molding and excimer laser micromachining, we fabricate multi-channel subdural microelectrodes primarily composed of ECM protein material and demonstrate that the electrochemical and mechanical properties match those of standard, uncoated controls. In vivo ECoG recordings in rodent brain confirm that the ECM microelectrode coatings and the protein interface do not alter signal fidelity. Astrogliotic, foreign body reaction to ECM coated devices is reduced, compared to uncoated controls, at 7 and 30 days, after subdural implantation in rat somatosensory cortex. We propose microfabricated, flexible, biomimetic electrodes as a new strategy to reduce inflammation at the device-tissue interface and improve the long-term stability of implantable subdural electrodes. <s> BIB039 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> The development of chronically implanted electrodes attracts much attention since these electrodes are much favorable for monitoring changes of neurotransmitters in brain science. The research in this field focused mainly on chemical modification to improve the potential stability and less on the biocompatibility. In this work, for the first time, we proposed the concept of cell-membrane electrodes based on a basic hypothesis using animal’s self-cell membrane to reduce animal exclusiveness (hyperacute rejection and chronic rejection). As a proof of concept, we first studied cell-membrane reference electrodes for chronically implanted electrodes. Red cell membrane (RCM) was extracted from rat blood and coated on the chemically modified Ag/AgCl electrodes. It was found that ionic liquid (IL) 1-butyl-2,3-dimethylimidazolium hexafluorophosphate (BDMI) showed good performance rather than Nafion used as coating film for protection of silver chloride on Ag wire and support of the cell membrane. Electrochemical i... <s> BIB040 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> As an important application of functional biomaterials, neural probes have contributed substantially to studying the brain. Bioinspired and biomimetic strategies have begun to be applied to the development of neural probes, although these and previous generations of probes have had structural and mechanical dissimilarities from their neuron targets that lead to neuronal loss, neuroinflammatory responses and measurement instabilities. Here, we present a bioinspired design for neural probes—neuron-like electronics (NeuE)—where the key building blocks mimic the subcellular structural features and mechanical properties of neurons. Full three-dimensional mapping of implanted NeuE–brain interfaces highlights the structural indistinguishability and intimate interpenetration of NeuE and neurons. Time-dependent histology and electrophysiology studies further reveal a structurally and functionally stable interface with the neuronal and glial networks shortly following implantation, thus opening opportunities for next-generation brain–machine interfaces. Finally, the NeuE subcellular structural features are shown to facilitate migration of endogenous neural progenitor cells, thus holding promise as an electrically active platform for transplantation-free regenerative medicine. <s> BIB041 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Neural recording electrode technologies have contributed considerably to neuroscience by enabling the extracellular detection of low-frequency local field potential oscillations and high-frequency action potentials of single units. Nevertheless, several long-standing limitations exist, including low multiplexity, deleterious chronic immune responses and long-term recording instability. Driven by initiatives encouraging the generation of novel neurotechnologies and the maturation of technologies to fabricate high-density electronics, novel electrode technologies are emerging. Here, we provide an overview of recently developed neural recording electrode technologies with high spatial integration, long-term stability and multiple functionalities. We describe how these emergent neurotechnologies can approach the ultimate goal of illuminating chronic brain activity with minimal disruption of the neural environment, thereby providing unprecedented opportunities for neuroscience research in the future. <s> BIB042 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Soft and magnetic resonance imaging (MRI) compatible neural electrodes enable stable chronic electrophysiological measurements and anatomical or functional MRI studies of the entire brain without electrode interference with MRI images. These properties are important for many studies, ranging from a fundamental neurophysiological study of functional MRI signals to a chronic neuromodulatory effect investigation of therapeutic deep brain stimulation. Here we develop soft and MRI compatible neural electrodes using carbon nanotube (CNT) fibers with a diameter from 20 μm down to 5 μm. The CNT fiber electrodes demonstrate excellent interfacial electrochemical properties and greatly reduced MRI artifacts than PtIr electrodes under a 7.0 T MRI scanner. With a shuttle-assisted implantation strategy, we show that the soft CNT fiber electrodes can precisely target specific brain regions and record high-quality single-unit neural signals. Significantly, they are capable of continuously detecting and isolating single n... <s> BIB043 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> C. Recent Advancement in Probe/Tissue Biointegration <s> Neural interfacing probes are located between the nervous system and the implanted electronic device in order to acquire information on the complex neuronal activity and to reconstruct impaired neural connectivity. Despite remarkable advancement in recent years, conventional neural interfacing is still unable to completely accomplish these goals, especially in long-term brain interfacing. The major limitation arises from physical and mechanical differences between neural interfacing probes and neural tissues that cause local immune responses and production of scar cells near the interface. Therefore, neural interfaces should ideally be extremely soft and have the physical scale of cells to mitigate the boundary between biotic and abiotic systems. Soft materials for neural interfaces have been intensively investigated to improve both interfacing and long-term signal transmission. The design and fabrication of micro and nanoscale devices have drastically decreased the stiffness of probes and enabled single-... <s> BIB044
Biocompatibility of the neural interface can be evaluated quantitatively based on the estimation of the neuron population as a function of the distance from the implant. Furthermore, the spread of the neuroinflammation BIB006 and causes of neural interfacing failure can be examined by either electrochemical impedance spectroscopy BIB003 or optical analysis BIB038 . To enhance the biointegration of the implantable neural probe, biocompatibility holds the key. Biological compatibility or biocompatibility depends on the material properties (e.g., chemical, mechanical and physical) of the implant. In general, biocompatibility is characterized as the capacity of a biomaterial to fulfil its ideal operation regarding a medicinal treatment, without inspiring any bothersome local or systematic effects in the recipient, yet producing the most proper cell or tissue reaction in that specific circumstance, and enhancing the clinically applicable presentation of that treatment  . Thus, a few methodologies have been proposed to improve the biocompatibility, for instance, enhanced device encapsulations can beat the electrical impacts from scar formations, and a decrease in device corrosion can limit the initiated neuroinflammatory responses. However, mechanical discrepancy between probe/tissue interface affects the long-term biocompatibility of the implanted neural device. Lack of mechanical uniformity between the brain and implanted device and micromotions are both associated with scar formation. A mechanically compliant device to the neural tissue is expected to enable the implanted device to pursue the movements of the brain. Bending stiffness and Young's modulus are the two physical quantities that are normally used to depict inflexibility or the protection from a twist or deformation. In identifying the amount of mechanical incompatibility, the bending stiffness of a specific implantable neural device is more critical than Young's modulus BIB033 , BIB029 . Fig. 5 (a) represents the scope of Young's moduli of different neural devices and neural tissue. To add more, the compelling bending stiffness estimations of traditional and emergent neural devices BIB013 BIB002 BIB020 BIB004 BIB008  alongside that of a 20-100 µm thick slice of brain tissue  , are plotted in Fig. 5(b) . Consequently, the mitigation of mechanical mismatch can be approached from two directions. Firstly, making polymer based flexible neural device as polymers such as such as Parylene C, polyimide, or SU-8 are softer than bulk Si and metals. Recently, S. Guan et al. introduced the Neurotassel probe based on polyimide comprising of numbers of flexible and high-aspect ratio microelectrode filaments, which can provide chronic recordings 3-6 weeks after implantation  . However, polymer based neural devices are still significantly stiffer than tissue. Shifting to increasingly agreeable materials, for example, Polydimethylsiloxane (PDMS) or hydrogel coatings shuts this gap BIB034 , BIB021 , as in Fig. 5(a) . Implantable neural probes based on the elastomeric substrate (e.g., PDMS) can be stretchable and enable chronic multimodal neuromodulation applications  . The second method recommends stiff materials such as polymers, metals, and semiconductor can be utilized if the characteristics dimensions of the implanted probes are in subcellular scale (1 to 10 µm) to take into account mechanical consistency BIB034 . Fig. 5(c) shows the some of the current research trends in designing the biointegrated implantable neural probe. Most of the recent neural devices based on ultra-small carbon BIB008 , BIB009 , polyimide BIB002 and elastomer-based 'e-dura' probes  , as well as traditional microwire and Michigan-type silicon devices are still considerably stiffer than the brain tissue. Moreover, probe/tissue biointegration often requires stretch ability (a lowmodulus, elastic reaction to huge strain distortions) and this can be accomplished with characteristically resilient materials or through introducing deterministic, composite shapes utilizing serpentine structures, and wavy structures. To promote the neuronal attachment, extracellular matrix, which is a passive covalent attachment can also be used. As for an example, fixed astrocyte extracellular matrix offers more reduction in microglial activation as compared to the individual extracellular matrix components such as laminin or fibronectin BIB001 BIB039 BIB040 . By exploiting the reliance of bending stiffness on implanted device size, only the mesh electronics associated with compelling mechanical properties practically identical to that of neural tissue ( Fig. 5(b) ). The chronic performance of the neural devices mostly depends on their dimensions, stability of their material and functionalities, proper encapsulations, and mechanical properties to reduce the foreign body response. Glial scar formation and displacement of tissue can be diminished by miniaturizing the size of the device, which can be achieved by reducing the cross-sectional area to decrease the stiffness of the device. As a result, reduction of implant dimensions to below several microns increase the bendability of neural devices, which results in less displacement and glial scar  BIB030 BIB035 . The application of emerging materials such as carbon fibre (7 µm in diameter) for longterm recording of neural activities has induced minor gliosis and neuron loss BIB008 . However, developing carbon fibre arrays is a difficult task and one electrode site per fibre limits the carbon fibre array configuration. On the other hand, recently a mesh electronics array configuration called neuron-like electronics (NeuE) has been proposed with features sizes analogous to the neuron axon and attunes extremely low bending forces, which results in minimum inflammation and foster implant-neuron interaction BIB041 . Consequently, such mesh electronics are chronically stable for recording up to 3 ∼ 8 months BIB042 , BIB034 , BIB041 . However, the trade-off remains as a syringe is required to inject the mesh electronics without having the precise control over the implantation BIB020 . Furthermore, neuron-scale devices are yet to showcase their length of service to confirm the applicability in larger animals. To reduce mechanical discrepancy between the brain tissue and the implantable device, a hot topic of research is the use of a soft and flexible BIB022 BIB010 BIB031 or stretchable BIB036 BIB014 BIB011 BIB023 system for implantable neural device. Although flexible and stretchable/elastic implants have achieved minimum foreign body response when implanted chronically, thorough and outright correlation in performance for chronic recording between flexible and conventional silicon/metal devices is required to be investigated. On the other hand, such flexible and soft devices also introduce complexities in implanting the device inside the brain. To this end, these problems are managed by using encapsulation approaches such as silk BIB024 , carboxymethyl cellulose BIB015 , syringe injection shuttles BIB020 , BIB012 , or magnetic insertion BIB025 . As current trends are progressing towards making these devices smaller and more flexible, more advanced and durable biocompatible materials are desirable. Then again, ultra-small and flexible devices are susceptible to material and physical failure due to their geometry. Thin encapsulation is another essential criterion for these devices. Most commonly used flexible polymers (e.g., Polyimide and Parylene C) for ultrathin (<1 µm) encapsulations have difficulties in chronic stability and reliability BIB032 , expressing the need of further improvement on insulation materials/methods. Upon stretching/flexing, materials require to exhibit both conductivity as well as flexibility. A promising advancement in elastic conductors has been revealed through nanoconfinement effect BIB037 . The application of such materials for implantable neural implants is yet to be explored. The impedance of the electrode increases, if its size is minimized to record or stimulate single or small numbers of neurons. There is a well-known trade-off between the electrode area and impedance. While averaging over a big population of neurons, in general, bigger regions decrease R spread and add to the capacitance, C e . In any case, the need to quantify action potentials of individual neurons with a high-resolution proportion has prompted a staggering spotlight on augmenting C e while minimizing the implantable device size. Surface alteration of the electrode by strategies, for example, nanostructured coatings and including composite films made of carbon nanomaterials have been broadly explored BIB016 . Nanostructured coatings permit a critical increment in the surface area of the probe/tissue interface and are regularly utilized for multielectrode arrays. An indistinguishable methodology has been taken with carbon nanostructures (carbon nanotubes and graphene) BIB005 , BIB017 as well as their composites, and results in an identical results BIB007 . Carbon nanotubes (CNT) based Magnetic Resonance Imaging (MRI) compatible neural probes have also been developed to combine functional MRI (fMRI) studies across entire brain regions without any electrode interferences BIB043 . Likewise, conductive polymers present another unique option to improve the performance of the electrode. Conductive polymers such as poly(3,4-ethylenedioxythiophene) (PEDOT) and Polypyrrole can give a mix of ionic infiltration and adequate pathways for electronic conduct, which yield remarkable increment in capacitance per unit geometric surface area than normal metallic electrodes and, therefore, improve both recorded signal strength and stimulation capacity  . Conductive polymers can be promptly functionalized through physical ensnarement and covalent cross-connecting with biomolecules and cells, which can viably dim the biotic/abiotic interface and improve biointegration BIB026 , BIB016 , BIB018 , BIB027 . Additionally, to ease the functionality and improve the stability, advanced conductive polymers have been investigated in dopants for neural recording BIB030 , BIB028 and drug delivery BIB019 . These novel polymer coatings enable more reduction in dimension for implantable neural devices. The aforementioned strategies improve the mechanical and physical properties of the implanted neural devices to promote biocompatibility for probe/tissue biointegration. However, the recorded signal quality is affected due to miniaturized device size, number of channels, high signal-to-noise ratio, or less invasive approaches BIB044 . As a result, in addition to softness and biocompatibility of the device, further design methods and traits are also necessary. However, a detailed discussion on these topics is beyond the scope of this review. 