A 3D In Vitro Cortical Tissue Model Based on Dense Collagen to Study the Effects of Gamma Radiation on Neuronal Function.

Studies on gamma radiation-induced injury have long been focused on hematopoietic, gastrointestinal, and cardiovascular systems, yet little is known about the effects of gamma radiation on the function of human cortical tissue. The challenge in studying radiation-induced cortical injury is, in part, due to a lack of human tissue models and physiologically relevant readouts. Here, a physiologically relevant 3D collagen-based cortical tissue model (CTM) is developed for studying the functional response of human iPSC-derived neurons and astrocytes to a sub-lethal radiation exposure (5 Gy). Cytotoxicity, DNA damage, morphology, and extracellular electrophysiology are quantified. It is reported that 5 Gy exposure significantly increases cytotoxicity, DNA damage, and astrocyte reactivity while significantly decreasing neurite length and neuronal network activity. Additionally, it is found that clinically deployed radioprotectant amifostine ameliorates the DNA damage, cytotoxicity, and astrocyte reactivity. The CTM provides a critical experimental platform to understand cell-level mechanisms by which gamma radiation (GR) affects human cortical tissue and to screen prospective radioprotectant compounds.

Global analyses of mRNA expression in human sensory neurons reveal eIF5A as a conserved target for inflammatory pain.

Nociceptors are a type of sensory neuron that are integral to most forms of pain. Targeted disruption of nociceptor sensitization affords unique opportunities to prevent pain. An emerging model for nociceptors are sensory neurons derived from human stem cells. Here, we subjected five groups to high-throughput sequencing: human induced pluripotent stem cells (hiPSCs) prior to differentiation, mature hiPSC-derived sensory neurons, mature co-cultures containing hiPSC-derived astrocytes and sensory neurons, mouse dorsal root ganglion (DRG) tissues, and mouse DRG cultures. Co-culture of nociceptors and astrocytes promotes expression of transcripts enriched in DRG tissues. Comparisons of the hiPSC models to tissue samples reveal that many key transcripts linked to pain are present. Markers indicative of a range of neuronal subtypes present in the DRG were detected in mature hiPSCs. Intriguingly, translation factors were maintained at consistently high expression levels across species and culture systems. As a proof of concept for the utility of this resource, we validated expression of eukaryotic initiation factor 5A (eIF5A) in DRG tissues and hiPSC samples. eIF5A is subject to a unique posttranslational hypusine modification required for its activity. Inhibition of hypusine biosynthesis prevented hyperalgesic priming by inflammatory mediators in vivo and diminished hiPSC activity in vitro. Collectively, our results illuminate the transcriptomes of hiPSC sensory neuron models. We provide a demonstration for this resource through our investigation of eIF5A. Our findings reveal hypusine as a potential target for inflammation associated pain in males.

Investigating the Function of Adult DRG Neuron Axons Using an In Vitro Microfluidic Culture System.

A critical role of the peripheral axons of nociceptors of the dorsal root ganglion (DRG) is the conduction of all-or-nothing action potentials from peripheral nerve endings to the central nervous system for the perception of noxious stimuli. Plasticity along multiple sites along the pain axis has now been widely implicated in the maladaptive changes that occur in pathological pain states such as neuropathic and inflammatory pain. Notably, increasing evidence suggests that nociceptive axons actively participate through the local expression of ion channels, receptors, and signal transduction molecules through axonal mRNA translation machinery that is independent of the soma component. In this report, we explore the sensitization of sensory neurons through the treatment of compartmentalized axon-like structures spanning microchannels that have been treated with the cytokine IL-6 and, subsequently, capsaicin. These data demonstrate the utility of isolating DRG axon-like structures using microfluidic systems, laying the groundwork for constructing the complex in vitro models of cellular networks that are involved in pain signaling for targeted pharmacological and genetic perturbations.

Stable softening bioelectronics: A paradigm for chronically viable ester-free neural interfaces such as spinal cord stimulation implants.

Polymer toughness is preserved at chronic timepoints in a new class of modulus-changing bioelectronics, which hold promise for commercial chronic implant components such as spinal cord stimulation leads. The underlying ester-free chemical network of the polymer substrate enables device rigidity during implantation, soft, compliant, conforming structures during acute phases in vivo, and gradual stabilization of materials properties chronically, maintaining materials toughness as device stiffness changes. In the past, bioelectronics device designs generally avoided modulus-changing and materials due to the difficulty in demonstrating consistent, predictable performance over time in the body. Here, the acute, and chronic mechanical and chemical properties of a new class of ester-free bioelectronic substrates are described and characterized via accelerated aging at elevated temperatures, with an assessment of their underlying cytotoxicity. Furthermore, spinal cord stimulation leads consisting of photolithographically-defined gold traces and titanium nitride (TiN) electrodes are fabricated on ester-free polymer substrates. Electrochemical properties of the fabricated devices are determined in vitro before implantation in the cervical spinal cord of rat models and subsequent quantification of device stimulation capabilities. Preliminary in vivo evidence demonstrates that this new generation of ester-free, softening bioelectronics holds promise to realize stable, scalable, chronically viable components for bioelectronic medicines of the future.

Mechanically Robust, Softening Shape Memory Polymer Probes for Intracortical Recording.

While intracortical microelectrode arrays (MEAs) may be useful in a variety of basic and clinical scenarios, their implementation is hindered by a variety of factors, many of which are related to the stiff material composition of the device. MEAs are often fabricated from high modulus materials such as silicon, leaving devices vulnerable to brittle fracture and thus complicating device fabrication and handling. For this reason, polymer-based devices are being heavily investigated; however, their implementation is often difficult due to mechanical instability that requires insertion aids during implantation. In this study, we design and fabricate intracortical MEAs from a shape memory polymer (SMP) substrate that remains stiff at room temperature but softens to 20 MPa after implantation, therefore allowing the device to be implanted without aids. We demonstrate chronic recordings and electrochemical measurements for 16 weeks in rat cortex and show that the devices are robust to physical deformation, therefore making them advantageous for surgical implementation.

Deployable, liquid crystal elastomer-based intracortical probes.

Intracortical microelectrode arrays (MEAs) are currently limited in their chronic functionality due partially to the foreign body response (FBR) that develops in regions immediately surrounding the implant (typically within 50-100 µm). Mechanically flexible, polymer-based substrates have recently been explored for MEAs as a way of minimizing the FBR caused by the chronic implantation. Nonetheless, the FBR degrades the ability of the device to record neural activity. We are motivated to develop approaches to deploy multiple recording sites away from the initial site of implantation into regions of tissue outside the FBR zone. Liquid Crystal Elastomers (LCEs) are responsive materials capable of programmable and reversible shape change. These hydrophobic materials are also non-cytotoxic and compatible with photolithography. As such, these responsive materials may be well suited to serve as substrates for smart, implantable electronics. This study explores the feasibility of LCE-based deployable intracortical MEAs. LCE intracortical probes are fabricated on a planar substrate and adopt a 3D shape after being released from the substrate. The LCE probes are then fixed in a planar configuration using polyethylene glycol (PEG). The PEG layer dissolves in physiological conditions, allowing the LCE probe to deploy post-implantation. Critically, we show that LCE intracortical probes will deploy within a brain-like agarose tissue phantom. We also show that deployment distance increases with MEA width. A finite element model was then developed to predict the deformed shape of the deployed probe when embedded in an elastic medium. Finally, LCE-based deployable intracortical MEAs were capable of maintaining electrochemical stability, recording extracellular signals from cortical neurons in vivo, and deploying recording sites greater than 100 µm from the insertion site in vivo. Taken together, these results suggest the feasibility of using LCEs to develop deployable intracortical MEAs. STATEMENT OF SIGNIFICANCE: Deployable MEAs are a recently developed class of neural interfaces that aim to shift the recording sites away from the region of insertion to minimize the negative effects of FBR on the recording performance of MEAs. In this study, we explore LCEs as a potential substrate for deployable MEAs. The novelty of this study lies in the systematic and programmable deployment offered by LCE-based intracortical MEAs. These results illustrate the feasibility and potential application of LCEs as a substrate for deployable intracortical MEAs.

Conserved Expression of Nav1.7 and Nav1.8 Contribute to the Spontaneous and Thermally Evoked Excitability in IL-6 and NGF-Sensitized Adult Dorsal Root Ganglion Neurons In Vitro.

Sensory neurons respond to noxious stimuli by relaying information from the periphery to the central nervous system via action potentials driven by voltage-gated sodium channels, specifically Nav1.7 and Nav1.8. These channels play a key role in the manifestation of inflammatory pain. The ability to screen compounds that modulate voltage-gated sodium channels using cell-based assays assumes that key channels present in vivo is maintained in vitro. Prior electrophysiological work in vitro utilized acutely dissociated tissues, however, maintaining this preparation for long periods is difficult. A potential alternative involves multi-electrode arrays which permit long-term measurements of neural spike activity and are well suited for assessing persistent sensitization consistent with chronic pain. Here, we demonstrate that the addition of two inflammatory mediators associated with chronic inflammatory pain, nerve growth factor (NGF) and interleukin-6 (IL-6), to adult DRG neurons increases their firing rates on multi-electrode arrays in vitro. Nav1.7 and Nav1.8 proteins are readily detected in cultured neurons and contribute to evoked activity. The blockade of both Nav1.7 and Nav1.8, has a profound impact on thermally evoked firing after treatment with IL-6 and NGF. This work underscores the utility of multi-electrode arrays for pharmacological studies of sensory neurons and may facilitate the discovery and mechanistic analyses of anti-nociceptive compounds.

Liquid crystal elastomers as substrates for 3D, robust, implantable electronics.

New device architectures favorable for interaction with the soft and dynamic biological tissue are critical for the design of indwelling biosensors and neural interfaces. For the long-term use of such devices within the body, it is also critical that the component materials resist the physiological harsh mechanical and chemical conditions. Here, we describe the design and fabrication of mechanically and chemically robust 3D implantable electronics. This is achieved by using traditional photolithography to pattern electronics on liquid crystal elastomers (LCEs), a class of shape programmable materials. The chemical durability of LCE is evaluated under accelerated in vitro conditions simulating the physiological environment; for example, LCE exhibits less than 1% mass change under a hydrolytic medium simulating >1 year in vivo. By employing twisted nematic LCEs as dynamic substrates, we demonstrate electronics that are fabricated on planar substrates but upon release morph into programmed 3D shapes. These shapes are designed to enable intrinsically low failure strain materials to be extrinsically stretchable. For example, helical multichannel cables for electrode arrays withstand cyclic stretching and buckling over 10 000 cycles at 60% strain while being soaked in phosphate-buffered saline. We envision that these LCE-based electronics can be used for applications in implantable neural interfaces and biosensors.

Adaptation of robust Z' factor for assay quality assessment in microelectrode array based screening using adult dorsal root ganglion neurons.

BACKGROUND: Cell-based assays comprising primary sensory neurons cultured in vitro are an emerging tool for the screening and identification of potential analgesic compounds and chronic pain treatments. High-content screening (HCS) platforms for drug screening are characterized by a measure of assay quality indicator, such as the Z'-factor, which considers the signal dynamic range and data variation using control compounds only. Although widely accepted as a quality metric in high throughput screening (HTS), standard Z'-factor are not well-suited to indicate the quality of complex cell-based assays. NEW METHOD: The present study describes a method to assess assay quality in the context of extracellular recordings from dorsal root ganglion (DRG) sensory neurons cultured on multi-well microelectrode arrays. Data transformations are applied to electrophysiological parameters, such as electrode and well spike rates, for valid normality assumptions and suitability for use as a sample signal. Importantly, using transformed well-wide metrics, a robust version of the Z'-factor was applied, based on the median and median absolute deviation, to indicate assay quality and assess hit identification of putative pharmacological compounds. RESULTS: Application of appropriately scaled data and robust statistics ensured insensitivity to data variation and approximation of normal distribution. The use median and median absolute deviation of log transformed well spike rates in computing the Z'-factor revealed a value of 0.61, which is accepted as an "excellent assay." Known antagonists of nociceptor-specific voltage-gated sodium ion channels were identified as true hits in the present assay format under both spontaneous and thermally stimulated conditions. COMPARISON WITH EXISTING METHODS: The present approach demonstrated a large signal dynamic range and reduced sensitivity to data variation compared to standard Z'-factor used widely in HTS. CONCLUSION: Overall, the present study provides a statistical basis for the implementation of a HCS platform utilizing adult DRG neurons on microelectrode arrays.

Ruthenium oxide based microelectrode arrays for in vitro and in vivo neural recording and stimulation.

We have characterized the in vitro and in vivo extracellular neural recording and stimulation properties of ruthenium oxide (RuOx) based microelectrodes. Cytotoxicity and functional neurotoxicity assays were carried out to confirm the in vitro biocompatibility of RuOx. Material extract assays, in accordance to ISO protocol "10993-5: Biological evaluation of medical devices", revealed no significant effect on neuronal cell viability or the functional activity of cortical networks. In vitro microelectrode arrays (MEAs), with indium tin oxide (ITO) sites modified with sputtered iridium oxide (IrOx) and RuOx in a single array, were developed for a direct comparison of electrochemical and recording performance of RuOx to ITO and IrOx deposited microelectrode sites. The impedance of the RuOx-coated electrodes measured by electrochemical impedance spectroscopy was notably lower than that of ITO electrodes, resulting in robust extracellular recordings from cortical networks in vitro. We found comparable signal-to-noise ratios (SNRs) for RuOx and IrOx, both significantly higher than the SNR for ITO. RuOx-based MEAs were also fabricated and implanted in the rat motor cortex to demonstrate manufacturability of the RuOx processing and acute recording capabilities in vivo. We observed single-unit extracellular action potentials with a SNR >22, representing a first step for neurophysiological recordings in vivo with RuOx based microelectrodes. STATEMENT OF SIGNIFICANCE: A critical challenge in neural interface technology is the development of microelectrodes that have recording and electrical stimulation capabilities suitable for bidirectional communication between the external electronic device and the nervous system. The present study explores the feasibility and functional capabilities of ruthenium oxide microelectrodes as a neural interface. Significant improvement in electrochemical properties and neuronal recordings are reported when compared to commercially available indium tin oxide and was similar to that of iridium oxide electrodes. The data demonstrate the potential for future development of chronic neural interfaces using ruthenium oxide based microelectrodes for recording and stimulation.

Mechanical considerations for design and implementation of peripheral intraneural devices.

OBJECTIVE: Neural interfaces designed to stimulate or record electrical activity from peripheral nerves have applications ranging from the electrical modulation of nerve activity as a therapeutic option (e.g. epilepsy and depression) to the design of prosthetics. Currently, most peripheral nerve interfaces are either cuff-style devices that wrap around the target nerve or intraneural devices that are implanted within the nerve. While the latter option offers higher specificity and signal-to-noise ratio, penetrating devices can cause significant damage to the nerve due to the high degree of mechanical mismatch. Because of this, there is interest in developing penetrating devices fabricated from soft or softening materials (materials having a low elastic modulus). However, there is currently a lack of understanding regarding implantation forces required for successful insertion, which is a constraint for soft device design. Softer devices require robust designs to achieve a critical buckling force that is larger than forces experienced during device insertion. APPROACH: This study comprehensively assesses insertion force under different implantation conditions, with three variations for implantation speed, angle, and device tip angle, during insertion of silicon shanks in rat sciatic nerve. Additionally, we report compression moduli for rat sciatic nerve at different compression rates to inform computational modeling. MAIN RESULTS: We found that insertion speed and angle had significant effects on peak insertion force. We observed lower insertion forces (10-60 mN) when the device was implanted at higher angles relative to perpendicular insertion (80-125 mN). We also demonstrate the use of a nerve-stabilizing device to keep the nerve immobile during implantation. Additionally, we found that compression moduli were significantly different in small and large strain regions of the stress-strain curve with values between 1500-4500 Pa depending on compression rate. SIGNIFICANCE: This study provides information imperative to the design and successful implementation of soft penetrating peripheral nerve interfaces.

Chronic recording and electrochemical performance of amorphous silicon carbide-coated Utah electrode arrays implanted in rat motor cortex.

OBJECTIVE: Clinical applications of implantable microelectrode arrays are currently limited by device failure due to, in part, mechanical and electrochemical failure modes. To overcome this challenge, there is significant research interest in the exploration of novel array architectures and encapsulation materials. Amorphous silicon carbide (a-SiC) is biocompatible and corrosion resistant, and has recently been employed as a coating on biomedical devices including planar microelectrode arrays. However, to date, the three-dimensional Utah electrode array (UEA) is the only array architecture which has been approved by the food and drug administration (FDA) for long-term human trials. APPROACH: Here, we demonstrate, for the first time, that UEAs can be fabricated with a-SiC encapsulation and sputtered iridium oxide film (SIROF) electrode coatings, and that such arrays are capable of single-unit recordings over a 30 week implantation period in rat motor cortex. Over the same period, we carried out electrochemical measurements, including voltage transients, cyclic voltammetry, and electrochemical impedance spectroscopy (EIS), to evaluate potential failure modes. Furthermore, we evaluated chronic foreign body response via fluorescence immunohistochemistry following device explantation. MAIN RESULTS: During the indwelling period, we observed a reduction in active electrode yield percentage from 94.6 ± 5.4 (week 1) to 16.4 ± 11.5% (week 30). While the average active electrode yield showed a steady reduction, it is noteworthy that 3 out of 8 UEAs recorded greater than 60% active electrode yield at all times through 24 weeks and 1 out of 8 UEAs recorded greater than 60% active electrode yield at all times through the whole implantation period. SIGNIFICANCE: In total, these findings further suggest that a-SiC may serve as a mechanically and electrochemically stable device encapsulation alternative to polymeric coatings such as Parylene-C.

The Effect of Microfluidic Geometry on Myoblast Migration.

In vitro systems comprised of wells interconnected by microchannels have emerged as a platform for the study of cell migration or multicellular models. In the present study, we systematically evaluated the effect of microchannel width on spontaneous myoblast migration across these microchannels-from the proximal to the distal chamber. Myoblast migration was examined in microfluidic devices with varying microchannel widths of 1.5⁻20 µm, and in chips with uniform microchannel widths over time spans that are relevant for myoblast-to-myofiber differentiation in vitro. We found that the likelihood of spontaneous myoblast migration was microchannel width dependent and that a width of 3 µm was necessary to limit spontaneous migration below 5% of cells in the seeded well after 48 h. These results inform the future design of Polydimethylsiloxane (PDMS) microchannel-based co-culture platforms as well as future in vitro studies of myoblast migration.

Gold nanostructure microelectrode arrays for in vitro recording and stimulation from neuronal networks.

An ideal microelectrode array (MEA) design should include materials and structures which exhibit biocompatibility, low electrode polarization, low impedance/noise, and structural durability. Here, the fabrication of MEAs with indium tin oxide (ITO) electrodes deposited with self-similar gold nanostructures (GNS) is described. We show that fern leaf fractal-like GNS deposited on ITO electrodes are conducive for neural cell attachment and viability while reducing the interfacial impedance more than two orders of magnitude at low frequencies (100-1000 Hz) versus bare ITO. GNS MEAs, with low interfacial impedance, allowed the detection of extracellular action potentials with excellent signal-to-noise ratios (SNR, 20.26 ± 2.14). Additionally, the modified electrodes demonstrated electrochemical and mechanical stability over 29 d in vitro.

Emerging neurotechnology for antinoceptive mechanisms and therapeutics discovery.

The tolerance, abuse, and potential exacerbation associated with classical chronic pain medications such as opioids creates a need for alternative therapeutics. Phenotypic screening provides a complementary approach to traditional target-based drug discovery. Profiling cellular phenotypes enables quantification of physiologically relevant traits central to a disease pathology without prior identification of a specific drug target. For complex disorders such as chronic pain, which likely involves many molecular targets, this approach may identify novel treatments. Sensory neurons, termed nociceptors, are derived from dorsal root ganglia (DRG) and can undergo changes in membrane excitability during chronic pain. In this review, we describe phenotypic screening paradigms that make use of nociceptor electrophysiology. The purpose of this paper is to review the bioelectrical behavior of DRG neurons, signaling complexity in sensory neurons, various sensory neuron models, assays for bioelectrical behavior, and emerging efforts to leverage microfabrication and microfluidics for assay development. We discuss limitations and advantages of these various approaches and offer perspectives on opportunities for future development.

Liquid Crystal Elastomer-Based Microelectrode Array for In Vitro Neuronal Recordings.

Polymer-based biomedical electronics provide a tunable platform to interact with nervous tissue both in vitro and in vivo. Ultimately, the ability to control functional properties of neural interfaces may provide important advantages to study the nervous system or to restore function in patients with neurodegenerative disorders. Liquid crystal elastomers (LCEs) are a class of smart materials that reversibly change shape when exposed to a variety of stimuli. Our interest in LCEs is based on leveraging this shape change to deploy electrode sites beyond the tissue regions exhibiting inflammation associated with chronic implantation. As a first step, we demonstrate that LCEs are cellular compatible materials that can be used as substrates for fabricating microelectrode arrays (MEAs) capable of recording single unit activity in vitro. Extracts from LCEs are non-cytotoxic (>70% normalized percent viability), as determined in accordance to ISO protocol 10993-5 using fibroblasts and primary murine cortical neurons. LCEs are also not functionally neurotoxic as determined by exposing cortical neurons cultured on conventional microelectrode arrays to LCE extract for 48 h. Microelectrode arrays fabricated on LCEs are stable, as determined by electrochemical impedance spectroscopy. Examination of the impedance and phase at 1 kHz, a frequency associated with single unit recording, showed results well within range of electrophysiological recordings over 30 days of monitoring in phosphate-buffered saline (PBS). Moreover, the LCE arrays are shown to support viable cortical neuronal cultures over 27 days in vitro and to enable recording of prominent extracellular biopotentials comparable to those achieved with conventional commercially-available microelectrode arrays.

A Meta-Analysis of Intracortical Device Stiffness and Its Correlation with Histological Outcomes.

Neural implants offer solutions for a variety of clinical issues. While commercially available devices can record neural signals for short time periods, they fail to do so chronically, partially due to the sustained tissue response around the device. Our objective was to assess the correlation between device stiffness, a function of both material modulus and cross-sectional area, and the severity of immune response. Meta-analysis data were derived from nine previously published studies which reported device material and geometric properties, as well as histological outcomes. Device bending stiffness was calculated by treating the device shank as a cantilevered beam. Immune response was quantified through analysis of immunohistological images from each study, specifically looking at fluorescent markers for neuronal nuclei and astrocytes, to assess neuronal dieback and gliosis. Results demonstrate that the severity of the immune response, within the first 50 µm of the device, is highly correlated with device stiffness, as opposed to device modulus or cross-sectional area independently. In general, commercially available devices are around two to three orders of magnitude higher in stiffness than devices which induced a minimal tissue response. These results have implications for future device designs aiming to decrease chronic tissue response and achieve increased long-term functionality.

Chronic Intracortical Recording and Electrochemical Stability of Thiol-ene/Acrylate Shape Memory Polymer Electrode Arrays.

Current intracortical probe technology is limited in clinical implementation due to the short functional lifetime of implanted devices. Devices often fail several months to years post-implantation, likely due to the chronic immune response characterized by glial scarring and neuronal dieback. It has been demonstrated that this neuroinflammatory response is influenced by the mechanical mismatch between stiff devices and the soft brain tissue, spurring interest in the use of softer polymer materials for probe encapsulation. Here, we demonstrate stable recordings and electrochemical properties obtained from fully encapsulated shape memory polymer (SMP) intracortical electrodes implanted in the rat motor cortex for 13 weeks. SMPs are a class of material that exhibit modulus changes when exposed to specific conditions. The formulation used in these devices softens by an order of magnitude after implantation compared to its dry, room-temperature modulus of ~2 GPa.

In vitro compatibility testing of thiol-ene/acrylate-based shape memory polymers for use in implantable neural interfaces.

Shape memory polymers (SMPs) based on thiol-ene/acrylate formulations are an emerging class of materials with potential applications as structural and/or dielectric coatings for implantable neural interfaces. Here, we report in vitro compatibility studies of three novel thiol-ene/acrylate-based SMP formulations. In vivo cytotoxicity assays were carried out in accordance with International Organization for Standards (ISO) protocol 10993-5, using NCTC clone 929 fibroblasts as well as embryonic cortical cultures. All three SMP formulations passed standardized cytotoxicity assays (>70% normalized cell viability) using both cell types. Functional neurotoxicity assays were carried out using primary cortical networks cultured on substrate-integrated microelectrode arrays (MEAs). We observed significant reduction in cortical network activity in the case of positive control material, but no significant alterations in activity following incubation with SMP material extracts, indicating functional cytocompatibility. Finally, we assessed cell reactivity at the tissue-material interface by performing an in vitro glial scarring assay. Through immunostaining, we observed similar astrocyte-associated (GFAP) mean intensity ratios near nonsoftening SMP-coated and uncoated stainless steel microwires (1.10 ± 0.06 vs. 1.19 ± 0.10), suggesting similar glial cell reactivity. However, we observed decreased mean intensity ratios in the presence of fully softening SMP-coated microwires (1.02 ± 0.04) suggesting reduced glial cell reactivity. Overall, these results indicate that the thiol-ene/acrylate SMP formulations presented here are neither cytotoxic nor neurotoxic, and suggest that fully softening SMP may reduce foreign body response in terms of glial cell reactivity. These findings support further consideration of this class of materials as backbone or insulating materials for implantable neural stimulating/recording devices. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2891-2898, 2018.

Chronic recording and electrochemical performance of Utah microelectrode arrays implanted in rat motor cortex.

Multisite implantable electrode arrays serve as a tool to understand cortical network connectivity and plasticity. Furthermore, they enable electrical stimulation to drive plasticity, study motor/sensory mapping, or provide network input for controlling brain-computer interfaces. Neurobehavioral rodent models are prevalent in studies of motor cortex injury and recovery as well as restoration of auditory/visual cues due to their relatively low cost and ease of training. Therefore, it is important to understand the chronic performance of relevant electrode arrays in rodent models. In this report, we evaluate the chronic recording and electrochemical performance of 16-channel Utah electrode arrays, the current state-of-the-art in pre-/clinical cortical recording and stimulation, in rat motor cortex over a period of 6 mo. The single-unit active electrode yield decreased from 52.8 ± 10.0 ( week 1) to 13.4 ± 5.1% ( week 24). Similarly, the total number of single units recorded on all electrodes across all arrays decreased from 106 to 15 over the same time period. Parallel measurements of electrochemical impedance spectra and cathodic charge storage capacity exhibited significant changes in electrochemical characteristics consistent with development of electrolyte leakage pathways over time. Additionally, measurements of maximum cathodal potential excursion indicated that only a relatively small fraction of electrodes (10-35% at 1 and 24 wk postimplantation) were capable of delivering relevant currents (20 µA at 4 nC/ph) without exceeding negative or positive electrochemical potential limits. In total, our findings suggest mainly abiotic failure modes, including mechanical wire breakage as well as degradation of conducting and insulating substrates. NEW & NOTEWORTHY Multisite implantable electrode arrays serve as a tool to record cortical network activity and enable electrical stimulation to drive plasticity or provide network feedback. The use of rodent models in these fields is prevalent. We evaluated chronic recording and electrochemical performance of 16-channel Utah electrode arrays in rat motor cortex over a period of 6 mo. We primarily observed abiotic failure modes suggestive of mechanical wire breakage and/or degradation of insulation.