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.

Localizing Clinical Patterns of Blast Traumatic Brain Injury Through Computational Modeling and Simulation

Blast traumatic brain injury is ubiquitous in modern military conflict with significant morbidity and mortality. Yet the mechanism by which blast overpressure waves cause specific intracranial injury in humans remains unclear. Reviewing of both the clinical experience of neurointensivists and neurosurgeons who treated service members exposed to blast have revealed a pattern of injury to cerebral blood vessels, manifested as subarachnoid hemorrhage, pseudoaneurysm, and early diffuse cerebral edema. Additionally, a seminal neuropathologic case series of victims of blast traumatic brain injury (TBI) showed unique astroglial scarring patterns at the following tissue interfaces: subpial glial plate, perivascular, periventricular, and cerebral gray-white interface. The uniting feature of both the clinical and neuropathologic findings in blast TBI is the co-location of injury to material interfaces, be it solid-fluid or solid-solid interface. This motivates the hypothesis that blast TBI is an injury at the intracranial mechanical interfaces. In order to investigate the intracranial interface dynamics, we performed a novel set of computational simulations using a model human head simplified but containing models of gyri, sulci, cerebrospinal fluid (CSF), ventricles, and vasculature with high spatial resolution of the mechanical interfaces. Simulations were performed within a hybrid Eulerian—Lagrangian simulation suite (CTH coupled via Zapotec to Sierra Mechanics). Because of the large computational meshes, simulations required high performance computing resources. Twenty simulations were performed across multiple exposure scenarios—overpressures of 150, 250, and 500 kPa with 1 ms overpressure durations—for multiple blast exposures (front blast, side blast, and wall blast) across large variations in material model parameters (brain shear properties, skull elastic moduli). All simulations predict fluid cavitation within CSF (where intracerebral vasculature reside) with cavitation occurring deep and diffusely into cerebral sulci. These cavitation events are adjacent to high interface strain rates at the subpial glial plate. Larger overpressure simulations (250 and 500kPa) demonstrated intraventricular cavitation—also associated with adjacent high periventricular strain rates. Additionally, models of embedded intraparenchymal vascular structures—with diameters as small as 0.6 mm—predicted intravascular cavitation with adjacent high perivascular strain rates. The co-location of local maxima of strain rates near several of the regions that appear to be preferentially damaged in blast TBI (vascular structures, subpial glial plate, perivascular regions, and periventricular regions) suggest that intracranial interface dynamics may be important in understanding how blast overpressures leads to intracranial injury.

Expression of GFAP and Tau Following Blast Exposure in the Cerebral Cortex of Ferrets

Blast exposures are a hallmark of contemporary military conflicts. We need improved preclinical models of blast traumatic brain injury for translation of pharmaceutical and therapeutic protocols. Compared with rodents, the ferret brain is larger, has substantial sulci, gyri, a higher white to gray matter ratio, and the hippocampus in a ventral position; these attributes facilitate comparison with the human brain. In this study, ferrets received compressed air shock waves and subsequent evaluation of glia and forms of tau following survival of up to 12 weeks. Immunohistochemistry and Western blot demonstrated altered distributions of astrogliosis and tau expression after blast exposure. Many aspects of the astrogliosis corresponded to human pathology: increased subpial reactivity, gliosis at gray-white matter interfaces, and extensive outlining of blood vessels. MRI analysis showed numerous hypointensities occurring in the 12-week survival animals, appearing to correspond to luminal expansions of blood vessels. Changes in forms of tau, including phosphorylated tau, and the isoforms 3R and 4R were noted using immunohistochemistry and Western blot in specific regions of the cerebral cortex. Of particular interest were the 3R and 4R isoforms, which modified their ratio after blast. Our data strongly support the ferret as an animal model with highly translational features to study blast injury.

Allocation of funding into blast injury-related research and blast traumatic brain injury between 2000 and 2019: analysis of global investments from public and philanthropic funders

IntroductionThere is little systematic tracking or detailed analysis of investments in research and development for blast injury to support decision-making around research future funding.MethodsThis study examined global investments into blast injury-related research from public and philanthropic funders across 2000–2019. Research databases were searched using keywords, and open data were extracted from funder websites. Data collected included study title, abstract, award amount, funder and year. Individual awards were categorised to compare amounts invested into different blast injuries, the scientific approaches taken and analysis of research investment into blast traumatic brain injury (TBI).ResultsA total of 806 awards were identified into blast injury-related research globally, equating to US$902.1 million (m, £565.9m GBP). There was a general increase in year-on-year investment between 2003 and 2009 followed by a consistent decline in annual funding since 2010. Pre-clinical research received $671.3 m (74.4%) of investment. Brain-related injury research received $427.7 m (47.4%), orthopaedic injury $138.6 m (15.4%), eye injury $63.7 m (7.0%) and ear injury $60.5m (6.7%). Blast TBI research received a total investment of $384.3 m, representing 42.6% of all blast injury-related research. The U.S. Department of Defense funded $719.3 m (80%).ConclusionsInvestment data suggest that blast TBI research has received greater funding than other blast injury health areas. The funding pattern observed can be seen as reactive, driven by the response to the War on Terror, the rising profile of blast TBI and congressionally mandated research.

Abstract 17234: Elevated Atherosclerotic Biomarkers in Mice With Mild Blast Traumatic Brain Injury and Chronic Variable Stress

Introduction: Traumatic brain injury (TBI) and stress are significant health concerns that have atherosclerotic cardiovascular disease (ASCVD) effects. Stress and injury can elevate neurochemicals and hormones in the brain that lead to dysfunction of the hypothalamic-pituitary-adrenal axis and the autonomic nervous system increasing inflammation, which plays a role in the development of ASCVD. Animal models can provide a method of separating mild TBI (mTBI) from models of chronic stress. Hypothesis: We hypothesize that mild blast TBI (mbTBI) and chronic variable stress (CVS) will result in elevated ASCVD biomarkers in mice. Methods: Frozen hearts from C57BL/6J mice (8 weeks, N=16, 8 male/8 randomly cycling female) were obtained through an IACUC approved study. The C57BL/6J mice were part of a mild blast TBI (mbTBI) study utilizing a blast chamber to receive a short duration shock wave (<10 msec, mean peak pressure of blast waves 19.9 psi). A group was subjected to CVS for two weeks prior to the blast, plus one week after blast. All groups were followed for four weeks. Western Blots with relative expression (normalized) were performed using an infrared imaging system. ERK1, ERK2, Galactein 3, Endothelin-1, BDNF, NT-Pro-BNP, and NRG1. ANOVA with Tukey HSD correction and descriptive statistics were performed using SPSS with significance by α of 0.05. Results: ERK1: mbTBI and CVS (p<0.05). CVS +mbTBI to CVS (0.015)( p<0.05 ), compared to mbTBI (0.017). ERK2: mbTBI sham = 0.009, CVS only = 0.008, mbTBI only = 0.008 and CVS + mbTBI = 0.012. Galectin-3 (Gal-3): CVS only = 0.144, CVS+mbTBI = 0.168, mbTBI (0.114) to sham (0.111) ( p<0.05 ). NT-Pro-BNP: CVS+mbTBI = 0.168, sham 0.076. mbTBI alone (0.077) and CVS alone (0.078). NRG1: mbTBI (0.195) and mbTBI with CVS (0.178). CVS only group (0.157). ET-1: mbTBI sham = 0.068, CVS only = 0.080 mbTBI only = 0.084 and CVS+mbTBI = 0.134. BDNF: CVS only = 0.053, CVS+mbTBI = 0.069. Sham group (0.047), mbTBI (0.038). Conclusion: Our results on proteins related to a broad spectrum of vascular growth, innervation, function, inflammation and markers of atherosclerotic plaque development suggest that mbTBI and/or chronic stress may increase risk for developing early ASCVD.