Traumatic brain injury (TBI) is distinct from other neurological disorders because it is induced by a discrete event that applies extreme mechanical forces to the brain. This review describes how the ...brain senses, integrates, and responds to forces under both normal conditions and during injury. The response to forces is influenced by the unique mechanical properties of brain tissue, which differ by region, cell type, and sub-cellular structure. Elements such as the extracellular matrix, plasma membrane, transmembrane receptors, and cytoskeleton influence its properties. These same components also act as force-sensors, allowing neurons and glia to respond to their physical environment and maintain homeostasis. However, when applied forces become too large, as in TBI, these components may respond in an aberrant manner or structurally fail, resulting in unique pathological sequelae. This so-called “pathological mechanosensation” represents a spectrum of cellular responses, which vary depending on the overall biomechanical parameters of the injury and may be compounded by repetitive injuries. Such aberrant physical responses and/or damage to cells along with the resulting secondary injury cascades can ultimately lead to long-term cellular dysfunction and degeneration, often resulting in persistent deficits. Indeed, pathological mechanosensation not only directly initiates secondary injury cascades, but this post-physical damage environment provides the context in which these cascades unfold. Collectively, these points underscore the need to use experimental models that accurately replicate the biomechanics of TBI in humans. Understanding cellular responses in context with injury biomechanics may uncover therapeutic targets addressing various facets of trauma-specific sequelae.
•TBI is caused by extreme mechanical forces acting on the brain.•Cytoskeleton, plasma membrane, and transmembrane proteins sense forces in the brain.•Such biological force-sensors affect brain homeostasis and influence TBI responses.•These components can structurally fail due to mechanical forces produced during TBI.•Considering biomechanical parameters will advance the study and treatment of TBI.
Although concussion is now recognized as a major health issue, its non-lethal nature has limited characterization of the underlying pathophysiology. In particular, potential neuropathological changes ...have typically been inferred from non-invasive techniques or post-mortem examinations of severe traumatic brain injury (TBI). Here, we used a swine model of head rotational acceleration based on human concussion to examine blood–brain barrier (BBB) integrity after injury in association with diffuse axonal injury and glial responses. We then determined the potential clinical relevance of the swine concussion findings through comparisons with pathological changes in human severe TBI, where post-mortem examinations are possible. At 6–72 h post-injury in swine, we observed multifocal disruption of the BBB, demonstrated by extravasation of serum proteins, fibrinogen and immunoglobulin-G, in the absence of hemorrhage or other focal pathology. BBB disruption was observed in a stereotyped distribution consistent with biomechanical insult. Specifically, extravasated serum proteins were frequently observed at interfaces between regions of tissue with differing material properties, including the gray–white boundary, periventricular and subpial regions. In addition, there was substantial overlap of BBB disruption with regions of axonal pathology in the white matter. Acute perivascular cellular uptake of blood-borne proteins was observed to be prominent in astrocytes (GFAP-positive) and neurons (MAP-2-positive), but not microglia (IBA1-positive). Parallel examination of human severe TBI revealed similar patterns of serum extravasation and glial uptake of serum proteins, but to a much greater extent than in the swine model, attributed to the higher injury severity. These data suggest that BBB disruption represents a new and important pathological feature of concussion.
Conductive hydrogels are attractive to mimic electrophysiological environments of biological tissues and toward therapeutic applications. Injectable and conductive hydrogels are of particular ...interest for applications in 3D printing or for direct injection into tissues; however, current approaches to add conductivity to hydrogels are insufficient, leading to poor gelation, brittle properties, or insufficient conductivity. Here, an approach is developed using the jamming of microgels to form injectable granular hydrogels, where i) hydrogel microparticles (i.e., microgels) are formed with water‐in‐oil emulsions on microfluidics, ii) microgels are modified via an in situ metal reduction process, and iii) the microgels are jammed into a solid, permitting easy extrusion from a syringe. Due to the presence of metal nanoparticles at the jammed interface with high surface area in this unique design, the granular hydrogels have greater conductivity than non‐particle (i.e., bulk) hydrogels treated similarly or granular hydrogels either without metal nanoparticles or containing encapsulated nanoparticles. The conductivity of the granular hydrogels is easily modified through mixing conductive and non‐conductive microgels during fabrication and they can be applied to the 3D printing of lattices and to bridge muscle defects. The versatility of this conductive granular hydrogel will permit numerous applications where conductive materials are needed.
Injectable and conductive granular hydrogels are introduced through the jamming of microgels containing gallol redox chemistry inspired by fruit browning phenomena, coupled with an in situ metal reduction process. The conductive hydrogels provide facile 3D printability with desirable conductivity of extruded filaments, as well as electrical tissue conduction for further biomedical applications related to electroactive tissues.
High-resolution neural interfaces are essential tools for studying and modulating neural circuits underlying brain function and disease. Because electrodes are miniaturized to achieve higher spatial ...resolution and channel count, maintaining low impedance and high signal quality becomes a significant challenge. Nanostructured materials can address this challenge because they combine high electrical conductivity with mechanical flexibility and can interact with biological systems on a molecular scale. Unfortunately, fabricating high-resolution neural interfaces from nanostructured materials is typically expensive and time-consuming and does not scale, which precludes translation beyond the benchtop. Two-dimensional (2D) Ti3C2 MXene possesses a combination of remarkably high volumetric capacitance, electrical conductivity, surface functionality, and processability in aqueous dispersions distinct among carbon-based nanomaterials. Here, we present a high-throughput microfabrication process for constructing Ti3C2 neuroelectronic devices and demonstrate their superior impedance and in vivo neural recording performance in comparison with standard metal microelectrodes. Specifically, when compared to gold microelectrodes of the same size, Ti3C2 electrodes exhibit a 4-fold reduction in interface impedance. Furthermore, intraoperative in vivo recordings from the brains of anesthetized rats at multiple spatial and temporal scales demonstrate that Ti3C2 electrodes exhibit lower baseline noise, higher signal-to-noise ratio, and reduced susceptibility to 60 Hz interference than gold electrodes. Finally, in neuronal biocompatibility studies, neurons cultured on Ti3C2 are as viable as those in control cultures, and they can adhere, grow axonal processes, and form functional networks. Overall, our results indicate that Ti3C2 MXene microelectrodes have the potential to become a powerful platform technology for high-resolution biological interfaces.
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.
Neuroinflammation is initiated as a result of traumatic brain injury and can exacerbate evolving tissue pathology. Immune cells respond to acute signals from damaged cells, initiate ...neuroinflammation, and drive the pathological consequences over time. Importantly, the mechanism(s) of injury, the location of the immune cells within the brain, and the animal species all contribute to immune cell behavior following traumatic brain injury. Understanding the signals that initiate neuroinflammation and the context in which they appear may be critical for understanding immune cell contributions to pathology and regeneration. Within this paper, we review a number of factors that could affect immune cell behavior acutely following traumatic brain injury.
Despite the promising neuro-regenerative capacities of stem cells, there is currently no licensed stem cell-based product in the repair and regeneration of peripheral nerve injuries. Here, we ...explored the potential use of human gingiva-derived mesenchymal stem cells (GMSCs) as the only cellular component in 3D bio-printed scaffold-free neural constructs that were transplantable to bridge facial nerve defects in rats. We showed that GMSCs have the propensity to aggregate into compact 3D-spheroids that could produce their own matrix. When cultured under either 2D- or 3D-collagen scaffolds, GMSC spheroids were found to be more capable of differentiating into both neuronal and Schwann-like cells than their adherent counterparts. Using a scaffold-free 3D bio-printer system, nerve constructs were printed from GMSC spheroids in the absence of exogenous scaffolds and allowed to mature in a bioreactor. In vivo transplantation of the GMSC-laden nerve constructs promoted regeneration and functional recovery when used to bridge segmental defects in rat facial nerves. Our findings suggest that GMSCs represent an easily accessible source of MSCs for 3D bio-printing of scaffold-free nervous tissue constructs with promising potential application for repair and regeneration of peripheral nerve defects.
Damage to the peripheral nervous system is surprisingly common and occurs primarily from trauma or a complication of surgery. Although recovery of nerve function occurs in many mild injuries, ...outcomes are often unsatisfactory following severe trauma. Nerve repair and regeneration presents unique clinical challenges and opportunities, and substantial contributions can be made through the informed application of biomedical engineering strategies. This article reviews the clinical presentations and classification of nerve injuries, in addition to the state of the art for surgical decision-making and repair strategies. This discussion presents specific challenges that must be addressed to realistically improve the treatment of nerve injuries and promote widespread recovery. In particular, nerve defects a few centimeters in length use a sensory nerve autograft as the standard technique; however, this approach is limited by the availability of donor nerve and comorbidity associated with additional surgery. Moreover, we currently have an inadequate ability to noninvasively assess the degree of nerve injury and to track axonal regeneration. As a result, wait-and-see surgical decisions can lead to undesirable and less successful "delayed" repair procedures. In this fight for time, degeneration of the distal nerve support structure and target progresses, ultimately blunting complete functional recovery. Thus, the most pressing challenges in peripheral nerve repair include the development of tissue-engineered nerve grafts that match or exceed the performance of autografts, the ability to noninvasively assess nerve damage and track axonal regeneration, and approaches to maintain the efficacy of the distal pathway and targets during the regenerative process. Biomedical engineering strategies can address these issues to substantially contribute at both the basic and applied levels, improving surgical management and functional recovery following severe peripheral nerve injury.
Traumatic brain injury (TBI) often results in prolonged or permanent brain dysfunction with over 2.8 million affected annually in the U.S., including over 56,000 deaths, with over 5 million total ...survivors exhibiting chronic deficits. Mild TBI (also known as concussion) accounts for over 75% of all TBIs every year. Mild TBI is a heterogeneous disorder, and long-term outcomes are dependent on the type and severity of the initial physical event and compounded by secondary pathophysiological consequences, such as reactive astrocytosis, edema, hypoxia, excitotoxicity, and neuroinflammation. Neuroinflammation has gained increasing attention for its role in secondary injury as inflammatory pathways can have both detrimental and beneficial roles. For example, microglia-resident immune cells of the central nervous system (CNS)-influence cell death pathways and may contribute to progressive neurodegeneration but also aid in debris clearance and neuroplasticity. In this review, we will discuss the acute and chronic role of microglia after mild TBI, including critical protective responses, deleterious effects, and how these processes vary over time. These descriptions are contextualized based on interspecies variation, sex differences, and prospects for therapy. We also highlight recent work from our lab that was the first to describe microglial responses out to chronic timepoints after diffuse mild TBI in a clinically relevant large animal model. The scaled head rotational acceleration of our large animal model, paired with the gyrencephalic architecture and appropriate white:gray matter ratio, allows us to produce pathology with the same anatomical patterns and distribution of human TBI, and serves as an exemplary model to examine complex neuroimmune response post-TBI. An improved understanding of microglial influences in TBI could aid in the development of targeted therapeutics to accentuate positive effects while attenuating detrimental post-injury responses over time.
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•Immunosuppressive treatments generally reduce nerve regeneration after injury.•Macrophages exhibit diverse phenotypes to guide successful nerve regeneration.•Immunomodulatory ...therapies offer promise for treating peripheral nerve injuries.
Peripheral nerve injuries result in disrupted cellular communication between the central nervous system and somatic distal end targets. The peripheral nervous system is capable of independent and extensive regeneration; however, meaningful target muscle reinnervation and functional recovery remain limited and may result in chronic neuropathic pain and diminished quality of life. Macrophages, the primary innate immune cells of the body, are critical contributors to regeneration of the injured peripheral nervous system. However, in some clinical scenarios, macrophages may fail to provide adequate support with optimal timing, duration, and location. Here, we review the history of immunosuppressive and immunomodulatory strategies to treat nerve injuries. Thereafter, we enumerate the ways in which macrophages contribute to successful nerve regeneration. We argue that implementing macrophage-based immunomodulatory therapies is a promising treatment strategy for nerve injuries across a wide range of clinical presentations.
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