Advancement in neurotechnologies for electrophysiology, neurochemical sensing, neuromodulation, and optogenetics are revolutionizing scientific understanding of the brain while enabling treatments, cures, 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 diminish the quality of interface overtime. Recent advances in functional materials have been 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 largely avoided being addressed. Many engineering efforts that solely focus on optimizing individual probe design parameters, such as softness or flexibility, downplay critical multi-dimensional 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 will be achievable. In this review, the interdependence of different electrode components are highlighted to demonstrate the current materials-based challenges facing the field of neural interface engineering.
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 hours 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 hour−1) toward the probe beginning 12 hours after insertion. By 72 hours, 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.
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.
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.
Tissue decellularization has expanded the ability to generate non-immunogenic organ replacements for a broad range of health applications. Current technologies typically rely on the use of harsh agents for clearing cellular debris, altering the tissue structure and potentially diminishing the pro-regenerative effects. We have developed a method for effectively, yet gently, removing cellular components from peripheral nerve tissue while preserving the native tissue architecture. The novelty of this process is in the induction of programmed cell death - or apoptosis - via a general cytotoxin, thereby enabling antigen clearance using only hypertonic wash buffers. The resulting acellular nerve scaffolds are nearly identical to unprocessed tissue on a microscopic level and elicit low immune responses comparable to an isograft negative control in a model of subcutaneous implantation.
Our data indicate that this novel injectable form of acellular nerve grafts is amenable for use after contusion SCI and may bolster a simultaneous therapy by acutely modulating the inflammatory milieu and supporting axonal growth.
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