Advancements in neurotechnologies for electrophysiology, neurochemical sensing, neuromodulation, and optogenetics are revolutionizing scientific understanding of the brain while enabling treatments ...and preventative measures for a variety of neurological disorders. The grand challenge in neural interface engineering is to seamlessly integrate the interface between neurobiology and engineered technology to record from and modulate neurons over chronic timescales. However, the biological inflammatory response to implants, neural degeneration, and long‐term material stability diminishes the quality of the interface overtime. Recent advances in functional materials are aimed at engineering solutions for chronic neural interfaces, yet, the development and deployment of neural interfaces designed from novel materials have introduced new challenges that have been largely unaddressed. Many engineering efforts that solely focus on optimizing individual probe design parameters, such as softness or flexibility, downplay critical multidimensional interactions between different physical properties of the device that contribute to overall performance and biocompatibility. Moreover, the use of these new materials present substantial new difficulties that must be addressed before regulatory approval for use in human patients is achievable. In this review, the interdependence of different electrode components is highlighted to demonstrate the current material‐based challenges facing the field of neural interface engineering.
Neural interface engineering aims to apply advanced functional materials to seamlessly integrate neural technology with the nervous system in order to restore brain function in patients and uncover at least some of the brain's mysteries. This review highlights the challenges and interdependence of material components for long‐term functional performance, and compiles a “roadmap” to guide material‐based neural interface engineering.
Improving the long-term performance of neural electrode interfaces requires overcoming severe biological reactions such as neuronal cell death, glial cell activation, and vascular damage in the ...presence of implanted intracortical devices. Past studies traditionally observe neurons, microglia, astrocytes, and blood-brain barrier (BBB) disruption around inserted microelectrode arrays. However, analysis of these factors alone yields poor correlation between tissue inflammation and device performance. Additionally, these studies often overlook significant biological responses that can occur during acute implantation injury. The current study employs additional histological markers that provide novel information about neglected tissue components-oligodendrocytes and their myelin structures, oligodendrocyte precursor cells, and BBB -associated pericytes-during the foreign body response to inserted devices at 1, 3, 7, and 28 days post-insertion. Our results reveal unique temporal and spatial patterns of neuronal and oligodendrocyte cell loss, axonal and myelin reorganization, glial cell reactivity, and pericyte deficiency both acutely and chronically around implanted devices. Furthermore, probing for immunohistochemical markers that highlight mechanisms of cell death or patterns of proliferation and differentiation have provided new insight into inflammatory tissue dynamics around implanted intracortical electrode arrays.
Intracortical microelectrodes with the ability to detect intrinsic electrical signals and/or deliver electrical stimulation into local brain regions have been a powerful tool to understand brain ...circuitry and for therapeutic applications to neurological disorders. However, the chronic stability and sensitivity of these intracortical microelectrodes are challenged by overwhelming biological responses, including severe neuronal loss and thick glial encapsulation. Unlike microglia and astrocytes whose activity have been extensively examined, oligodendrocytes and their myelin processes remain poorly studied within the neural interface field. Oligodendrocytes have been widely recognized to modulate electrical signal conductance along axons through insulating myelin segments. Emerging evidence offers an alternative perspective on neuron-oligodendrocyte coupling where oligodendrocytes provide metabolic and neurotrophic support to neurons through cytoplasmic myelin channels and monocarboxylate transporters. This study uses in vivo multi-photon microscopy to gain insights into the dynamics of oligodendrocyte soma and myelin processes in response to chronic device implantation injury over 4 weeks. We observe that implantation induces acute oligodendrocyte injury including initial deformation and substantial myelinosome formation, an early sign of myelin injury. Over chronic implantation periods, myelin and oligodendrocyte soma suffer severe degeneration proximal to the interface. Interestingly, wound healing attempts such as oligodendrogenesis are initiated over time, however they are hampered by continued degeneration near the implant. Nevertheless, this detailed characterization of oligodendrocyte spatiotemporal dynamics during microelectrode-induced inflammation may provide insights for novel intervention targets to facilitate oligodendrogenesis, enhance the integration of neural-electrode interfaces, and improve long-term functional performance.
Display omitted
Neural interface technology provides direct sampling and analysis of electrical and chemical events in the brain in order to better understand neuronal function and treat neurodegenerative disease. ...However, intracortical electrodes experience inflammatory reactions that reduce long-term stability and functionality and are understood to be facilitated by activated microglia and astrocytes. Emerging studies have identified another cell type that participates in the formation of a high-impedance glial scar following brain injury; the oligodendrocyte precursor cell (OPC). These cells maintain functional synapses with neurons and are a crucial source of neurotrophic support. Following injury, OPCs migrate toward areas of tissue injury over the course of days, similar to activated microglia. The delayed time course implicates these OPCs as key components in the formation of the outer layers of the glial scar around the implant. In vivo two-photon laser scanning microscopy (TPLSM) was employed to observe fluorescently-labeled OPC and microglia reactivity up to 72 h following probe insertion. OPCs initiated extension of cellular processes (2.5 ± 0.4 μm h−1) and cell body migration (1.6 ± 0.3 μm h−1) toward the probe beginning 12 h after insertion. By 72 h, OPCs became activated at a radius of about 190.3 μm away from the probe surface. This study characterized the early spatiotemporal dynamics of OPCs involved in the inflammatory response induced by microelectrode insertion. OPCs are key mediators of tissue health and are understood to have multiple fate potentials. Detailed spatiotemporal characterization of glial behavior under pathological conditions may allow identification of alternative intervention targets for mitigating the formation of a glial scar and subsequent neurodegeneration that debilitates chronic neural interfaces.
Oligodendrocytes and their precursors are critical glial facilitators of neurophysiology, which is responsible for cognition and behavior. Devices that are used to interface with the brain allow for ...a more in-depth analysis of how neurons and these glia synergistically modulate brain activity. As projected by the BRAIN Initiative, technologies that acquire a high resolution and robust sampling of neural signals can provide a greater insight in both the healthy and diseased brain and support novel discoveries previously unobtainable with the current state of the art. However, a complex series of inflammatory events triggered during device insertion impede the potential applications of implanted biosensors. Characterizing the biological mechanisms responsible for the degradation of intracortical device performance will guide novel biomaterial and tissue regenerative approaches to rehabilitate the brain following injury. Glial subtypes which assist with neuronal survival and exchange of electrical signals, mainly oligodendrocytes, their precursors, and the insulating myelin membranes they produce, are sensitive to inflammation commonly induced from insults to the brain. This review explores essential physiological roles facilitated by oligodendroglia and their precursors and provides insight into their pathology following neurodegenerative injury and disease. From this knowledge, inferences can be made about the impact of device implantation on these supportive glia in order to engineer effective strategies that can attenuate their responses, enhance the efficacy of neural interfacing technology, and provide a greater understanding of the challenges that impede wound healing and tissue regeneration during pathology.
Brain computer interfaces (BCIs), including penetrating microelectrode arrays, enable both recording and stimulation of neural cells. However, device implantation inevitably causes injury to brain ...tissue and induces a foreign body response, leading to reduced recording performance and stimulation efficacy. Astrocytes in the healthy brain play multiple roles including regulating energy metabolism, homeostatic balance, transmission of neural signals, and neurovascular coupling. Following an insult to the brain, they are activated and gather around the site of injury. These reactive astrocytes have been regarded as one of the main contributors to the formation of a glial scar which affects the performance of microelectrode arrays. This study investigates the dynamics of astrocytes within the first 2 weeks after implantation of an intracortical microelectrode into the mouse brain using two-photon microscopy. From our observation astrocytes are highly dynamic during this period, exhibiting patterns of process extension, soma migration, morphological activation, and device encapsulation that are spatiotemporally distinct from other glial cells, such as microglia or oligodendrocyte precursor cells. This detailed characterization of astrocyte reactivity will help to better understand the tissue response to intracortical devices and lead to the development of more effective intervention strategies to improve the functional performance of neural interfacing technology.
Neurochemical sensing probes are a valuable diagnostic and therapeutic tool that can be used to study neurodegenerative diseases involving deficiencies in neurotransmitter signaling. However, ...implantation of these biosensors can elicit a harmful tissue response that alters the neurochemical environment within the brain. Transmission of chemical messengers via neurons is impeded by a barrier-forming glial scar that occurs within weeks after insertion followed by progressive neurodegeneration, attenuating signal sensitivity. Emerging research reveals that non-neuronal cells also influence the neurochemical milieu following injury both directly and indirectly. The reactivity of both microglia and astrocytes to inserted probes have been extensively studied in the past yet there remains other glial subtypes in the brain, such as oligodendrocytes and their precursors, the myelin structures they form, as well as vascular-bound pericytes, that have the potential to contribute significantly to the inflammation due to their responsibility to maintain tissue homeostasis. A brief overview of how tissue injury alters the neurochemical makeup followed by alternative potential targets of investigation and novel strategies to enhance the chemical sensing abilities of implantable probes will be discussed.
. Electrical stimulation has had a profound impact on our current understanding of nervous system physiology and provided viable clinical options for addressing neurological dysfunction within the ...brain. Unfortunately, the brain's immune suppression of indwelling microelectrodes currently presents a major roadblock in the long-term application of neural recording and stimulating devices. In some ways, brain trauma induced by penetrating microelectrodes produces similar neuropathology as debilitating brain diseases, such as Alzheimer's disease (AD), while also suffering from end-stage neuron loss and tissue degeneration. The goal of the present study was to understand whether there may be any parallel mechanisms at play between brain injury from chronic microelectrode implantation and those of neurodegenerative disorder.
. We used two-photon microscopy to visualize the accumulation, if any, of age- and disease-associated factors around chronically implanted electrodes in both young and aged mouse models of AD.
. We determined that electrode injury leads to aberrant accumulation of lipofuscin, an age-related pigment, in wild-type and AD mice alike. Furthermore, we reveal that chronic microelectrode implantation reduces the growth of pre-existing Alzheimer's plaques while simultaneously elevating amyloid burden at the electrode-tissue interface. Lastly, we uncover novel spatial and temporal patterns of glial reactivity, axonal and myelin pathology, and neurodegeneration related to neurodegenerative disease around chronically implanted microelectrodes.
. This study offers multiple novel perspectives on the possible neurodegenerative mechanisms afflicting chronic brain implants, spurring new potential avenues of neuroscience investigation and design of more targeted therapies for improving neural device biocompatibility and treatment of degenerative brain disease.
Biological inflammation induced during penetrating cortical injury can disrupt functional neuronal and glial activity within the cortex, resulting in potential recording failure of chronically ...implanted neural interfaces. Oligodendrocytes provide critical support for neuronal health and function through direct contact with neuronal soma and axons within the cortex. Given their fundamental role to regulate neuronal activity via myelin, coupled with their heightened vulnerability to metabolic brain injury due to high energetic demands, oligodendrocytes are hypothesized as a possible source of biological failure in declining recording performances of intracortical microelectrode devices. To determine the extent of their contribution to neuronal activity and function, a cuprizone-inducible model of oligodendrocyte depletion and demyelination in mice was performed prior to microelectrode implantation. At 5 weeks of cuprizone exposure, mice demonstrated significantly reduced cortical oligodendrocyte density and myelin expression. Mice were then implanted with functional recording microelectrodes in the visual cortex and neuronal activity was evaluated up to 7 weeks alongside continued cuprizone administration. Cuprizone-induced oligodendrocyte loss and demyelination was associated with significantly reduced recording performances at the onset of implantation, which remained relatively stable over time. In contast, recording performances for mice on a normal diet were intially elevated before decreasing over time to the recording level of tcuprizone-treated mice. Further electrophysiological analysis revealed deficits in multi-unit firing rates, frequency-dependent disruptions in neuronal oscillations, and altered laminar communication within the cortex of cuprizone-treated mice. Post-mortem immunohistochemistry revealed robust depletion of oligodendrocytes around implanted microelectrode arrays alongside comparable neuronal densities to control mice, suggesting that oligodendrocyte loss was a possible contributor to chronically impaired device performances. This study highlights potentially significant contributions from the oligodendrocyte lineage population concerning the biological integration and long-term functional performance of neural interfacing technology.
. Over the past decade, neural electrodes have played a crucial role in bridging biological tissues with electronic and robotic devices. This study focuses on evaluating the optimal tip profile and ...insertion speed for effectively implanting Paradromics' high-density fine microwire arrays (F
A) prototypes into the primary visual cortex (V1) of mice and rats, addressing the challenges associated with the 'bed-of-nails' effect and tissue dimpling.
. Tissue response was assessed by investigating the impact of electrodes on the blood-brain barrier (BBB) and cellular damage, with a specific emphasis on tailored insertion strategies to minimize tissue disruption during electrode implantation.
Electro-sharpened arrays demonstrated a marked reduction in cellular damage within 50
m of the electrode tip compared to blunt and angled arrays. Histological analysis revealed that slow insertion speeds led to greater BBB compromise than fast and pneumatic methods. Successful single-unit recordings validated the efficacy of the optimized electro-sharpened arrays in capturing neural activity.
These findings underscore the critical role of tailored insertion strategies in minimizing tissue damage during electrode implantation, highlighting the suitability of electro-sharpened arrays for long-term implant applications. This research contributes to a deeper understanding of the complexities associated with high-channel-count microelectrode array implantation, emphasizing the importance of meticulous assessment and optimization of key parameters for effective integration and minimal tissue disruption. By elucidating the interplay between insertion parameters and tissue response, our study lays a strong foundation for the development of advanced implantable devices with a reduction in reactive gliosis and improved performance in neural recording applications.
PDF
