Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

Most traumatic brain injuries (TBIs) during military deployment or training are clinically “mild” and frequently caused by non-impact blast exposures. Experimental models were developed to reproduce the biological consequences of high-intensity blasts causing moderate to severe brain injuries. However, the pathophysiological mechanisms of low-intensity blast (LIB)-induced neurological deficits have been understudied. This review provides perspectives on primary blast-induced mild TBI models and discusses translational aspects of LIB exposures as defined by standardized physical parameters including overpressure, impulse, and shock wave velocity. Our mouse LIB-exposure model, which reproduces deployment-related scenarios of open-field blast (OFB), caused neurobehavioral changes, including reduced exploratory activities, elevated anxiety-like levels, impaired nesting behavior, and compromised spatial reference learning and memory. These functional impairments associate with subcellular and ultrastructural neuropathological changes, such as myelinated axonal damage, synaptic alterations, and mitochondrial abnormalities occurring in the absence of gross- or cellular damage. Biochemically, we observed dysfunctional mitochondrial pathways that led to elevated oxidative stress, impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated cell respiration-relevant enzyme activity. LIB also induced increased levels of total tau, phosphorylated tau, and amyloid β peptide, suggesting initiation of signaling cascades leading to neurodegeneration. We also compare translational aspects of OFB findings to alternative blast injury models. By scoping relevant recent research findings, we provide recommendations for future preclinical studies to better reflect military-operational and clinical realities. Overall, better alignment of preclinical models with clinical observations and experience related to military injuries will facilitate development of more precise diagnosis, clinical evaluation, treatment, and rehabilitation.

In silico investigation of biomechanical response of a human subjected to primary blast

The response of the brain to the explosion induced primary blast waves is actively sought. Over the past decade, reasonable progress has been made in the fundamental understanding of bTBI using head surrogates and animal models. Yet, the current understanding of how blast waves interact with the human is in nascent stages, primarily due to lack of data in humans. The biomechanical response in human is critically required so that connection to the aforementioned bTBI models can be faithfully established. Here, using a detailed, full-body human model, we elucidate the biomechanical cascade of the brain under a primary blast. The input to the model is incident overpressure as achieved by specifying charge mass and standoff distance through ConWep. The full-body model allows to holistically probe short- (<5 ms) and long-term (200 ms) brain biomechanical responses. The full-body model has been extensively validated against impact loading in the past. In this work, we validate the head model against blast loading. We also incorporate structural anisotropy of the brain white matter. Blast wave human interaction is modeled using a conventional weapon modeling approach. We demonstrate that the blast wave transmission, linear and rotational motion of the head are dominant pathways for the biomechanical loading of the brain, and these loading paradigms generate distinct biomechanical fields within the brain. Blast transmission and linear motion of the head govern the volumetric response, whereas the rotational motion of the head governs the deviatoric response. We also observe that blast induced head rotation alone produces a diffuse injury pattern in white matter fiber tracts. Lastly, we find that the biomechanical response under blast is comparable to the impact event. These insights will augment laboratory and clinical investigations of bTBI and help devise better blast mitigation strategies.

Guidelines to inform the generation of clinically relevant and realistic blast loading conditions for primary blast injury research

‘Primary’ blast injuries (PBIs) are caused by direct blast wave interaction with the human body, particularly affecting air-containing organs. With continued experimental focus on PBI mechanisms, recently on blast traumatic brain injury, meaningful test outcomes rely on appropriate simulated conditions. Selected PBI predictive criteria (grouped into those affecting the auditory system, pulmonary injuries and brain trauma) are combined and plotted to provide rationale for generating clinically relevant loading conditions. Using blast engineering theory, explosion characteristics including blast wave parameters and fireball dimensions were calculated for a range of charge masses assuming hemispherical surface detonations and compared with PBI criteria. While many experimental loading conditions are achievable, this analysis demonstrated limits that should be observed to ensure loading is clinically relevant, realistic and practical. For PBI outcomes sensitive only to blast overpressure, blast scaled distance was demonstrated to be a useful parameter for guiding experimental design as it permits flexibility for different experimental set-ups. This analysis revealed that blast waves should correspond to blast scaled distances of 1.75<Z<6.0 to generate loading conditions found outside the fireball and of clinical relevance to a range of PBIs. Blast waves with positive phase durations (2–10 ms) are more practical to achieve through experimental approaches, while representing realistic threats such as improvised explosive devices (ie, 1–50 kg trinitrotoluene equivalent). These guidelines can be used by researchers to inform the design of appropriate blast loading conditions in PBI experimental investigations.

Defining blast loading ‘zones of relevance’ for primary blast injury research: A consensus of injury criteria for idealised explosive scenarios

Blast injuries remain a serious threat to defence and civilian populations around the world. ‘Primary’ blast injuries (PBIs) are caused by direct blast wave interaction with the human body, particularly affecting air-containing organs. Despite development of blast injury criteria since the 1960s, work to define blast loading conditions for safety limits, protective design and injury research has received relatively little attention. With a continued experimental focus on PBI mechanisms and idealised blast assumptions, meaningful test outcomes rely on appropriate simulated conditions. This paper critically evaluates existing predictive criteria for PBIs (grouped into those affecting the auditory system, pulmonary injuries and brain trauma) as a function of incident blast wave parameters, assuming idealised air blast scenarios. Analysis of the multi-injury criteria reveals new insights and understanding. It showed that blast conditions of relevance to realistic explosive threats are limited and they should be an important consideration in the design of clinical trials simulating blast injury. Zones of relevance for PBI research are proposed to guide experimental designs and compare future data. This work will prove valuable to blast protection engineers and clinical researchers seeking to determine blast loading conditions for safety limits, protective design requirements and injury investigations.

Structural disruption of the blood–brain barrier in repetitive primary blast injury

Background Blast-induced traumatic brain injury (bTBI) is a growing health concern due to the increased use of low-cost improvised explosive devices in modern warfare. Mild blast exposures are common amongst military personnel; however, these women and men typically do not have adequate recovery time from their injuries due to the transient nature of behavioral symptoms. bTBI has been linked to heterogeneous neuropathology, including brain edema, neuronal degeneration and cognitive abnormalities depending on the intensity of blast overpressure and frequency. Recent studies have reported heterogeneity in blood–brain barrier (BBB) permeability following blast injury. There still remains a limited understanding of the pathologic changes in the BBB following primary blast injuries. In this study, our goal was to elucidate the pathologic pattern of BBB damage through structural analysis following single and repetitive blast injury using a clinically relevant rat model of bTBI. Methods A validated, open-ended shock tube model was used to deliver single or repetitive primary blast waves. The pathology of the BBB was assessed using immunofluorescence and immunohistochemistry assays. All data were analyzed using the one-way ANOVA test. Results We have demonstrated that exposure to repetitive blast injury affects the desmin-positive and CD13-positive subpopulations of pericytes in the BBB. Changes in astrocytes and microglia were also detected. Conclusion This study provides analysis of the BBB components after repetitive blast injury. These results will be critical as preventative and therapeutic strategies are established for veterans recovering from blast-induced traumatic brain injury.

Damage-Associated Molecular Patterns and Their Signaling Pathways in Primary Blast Lung Injury: New Research Progress and Future Directions

Primary blast lung injury (PBLI) is a common cause of casualties in wars, terrorist attacks, and explosions. It can exist in the absence of any other outward signs of trauma, and further develop into acute lung injury (ALI) or a more severe acute respiratory distress syndrome (ARDS). The pathogenesis of PBLI at the cellular and molecular level has not been clear. Damage-associated molecular pattern (DAMP) is a general term for endogenous danger signals released by the body after injury, including intracellular protein molecules (HMGB1, histones, s100s, heat shock proteins, eCIRP, etc.), secretory protein factors (IL-1β, IL-6, IL-10, TNF-α, VEGF, complements, etc.), purines and pyrimidines and their derived degradation products (nucleic acids, ATP, ADP, UDPG, uric acid, etc.), and extracellular matrix components (hyaluronic acid, fibronectin, heparin sulfate, biglycan, etc.). DAMPs can be detected by multiple receptors including pattern recognition receptors (PRRs). The study of DAMPs and their related signaling pathways, such as the mtDNA-triggered cGAS-YAP pathway, contributes to revealing the molecular mechanism of PBLI, and provides new therapeutic targets for controlling inflammatory diseases and alleviating their symptoms. In this review, we focus on the recent progress of research on DAMPs and their signaling pathways, as well as the potential therapeutic targets and future research directions in PBLI.