Experimental Animal Models for Studies on the Mechanisms of Blast-Induced Neurotrauma

Abstract

A blast injury is a complex type of physical trauma resulting from the detonation of explosive compounds and has become an important issue due to the use of improvised explosive devices (IED) in current military conflicts. Blast-induced neurotrauma (BINT) is a major concern in contemporary military medicine and includes a variety of injuries that range from mild to lethal. Extreme forces and their complex propagation characterize BINT. Modern body protection and the development of armored military vehicles can be assumed to have changed the outcome of BINT. Primary blast injuries are caused by overpressure waves whereas secondary, tertiary, and quaternary blast injuries can have more varied origins such as the impact of fragments, abnormal movements, or heat. The characteristics of the blast wave can be assumed to be significantly different in open field detonations compared to explosions in a confined space, such an armored vehicle. Important parameters include peak pressure, duration, and shape of the pulse. Reflections from walls and armor can make the prediction of effects in individual cases very complex. Epidemiological data do not contain information of the comparative importance of the different blast mechanisms. It is therefore important to generate data in carefully designed animal models. Such models can be selective reproductions of a primary blast, penetrating injuries from fragments, acceleration movements, or combinations of such mechanisms. It is of crucial importance that the physical parameters of the employed models are well characterized so that the experiments can be reproduced in different laboratory settings. Ideally, pressure recordings should be calibrated by using the same equipment in several laboratories. With carefully designed models and thoroughly evaluated animal data it should be possible to achieve a translation of data between animal and clinical data. Imaging and computer simulation represent a possible link between experiments and studies of human cases. However, in order for mathematical simulations to be completely useful, the predictions will most likely have to be validated by detailed data from animal experiments. Some aspects of BINT can conceivably be studied in vitro. However, factors such as systemic response, brain edema, inflammation, vasospasm, or changes in synaptic transmission and behavior must be evaluated in experimental animals. Against this background, it is necessary that such animal experiments are carefully developed imitations of actual components in the blast injury. This paper describes and discusses examples of different designs of experimental models relevant to BINT.

Modeling clinically relevant blast parameters based on scaling principles produces functional & histological deficits in rats

“…Similarly, endothelial damage results in a loss of tight junction integrity and consequently the potential for increased blood-brain barrier permeability and microvascular injury (Duckworth et al, 2012). Notably, increased BBB permeability has been found as late as one month following blastinduced brain injury in a preclinical rodent model, indicating the presence of lasting microvascular dysfunction (Rubovitch et al, 2011). Furthermore, blast-induced BBB disruption has been observed to occur more extensively on the contralateral side, as well as at fluid-tissue interfaces such as that surrounding the lateral ventricles (Readnower et al, 2010), consistent with the findings reported within this study in which the contralateral side was more severely injured in comparison to the ipsilateral side based on standard markers of neural degeneration, astrocyte reactivity, and microglial activation (Garman et al, 2011).…”

“…The scaling equations developed have displayed significant utility in the development of injury risk functions based upon the high level of agreement with pre-existing experimental data concerning blast survival and injury risk. As such, while scaling of blast injury and associated blast parameters based on subject weight has not been related to neural injury (Park et al, 2011), scaling represents a logical step forward in more closely replicating clinically relevant exposures in laboratory models Rafaels et al, 2012;Risling and Davidsson, 2012).…”

“…How blast-injury models affect behavioral functions in rodents is poorly understood but of clear interest based on clinical findings associated with blast that include retrograde amnesia, confusion, loss of consciousness, depression, post-traumatic stress disorder (PTSD), vertigo, balance disorders, anxiety, apathy, and difficulty concentrating and performing executive functions (Magnuson et al, 2012;Risling and Davidsson, 2012;Rubovitch et al, 2011;Scheibel et al, 2012;Taber et al, 2006). Previous reports have demonstrated impairment on the accelerating rotarod following direct cranial blast injury (Kuehn et al, 2011) and on the balance beam following whole body blast exposure (Ahlers et al, 2012) while others have shown that shielding of the torso prevents neural injury and associated behavioral deficits following blast .…”

Neurotransmitter Systems in a Mild Blast Traumatic Brain Injury Model: Catecholamines and Serotonin

“…Such accumulations have been reported in blast and are generally attributed to rotational acceleration rather than to primary blast. 46,75 However, effects by smoke emission and heating (quaternary blast) cannot be excluded. Gene expression in the hippocampus has been shown to be very different in this model for primary blast, compared with rotational injury.…”

Application of High-Intensity Focused Ultrasound to the Study of Mild Traumatic Brain Injury

“…One method for generating overpressures representative of actual explosions is the use of gas-driven overpressure shock tubes Chavko et al 2008;Desmoulin and Dionne 2009;Gorbunov et al 2008;Long et al 2009;Risling and Davidsson 2012;Sundaramurthy et al 2012;Svetlov et al 2010). Although blast shock tube models are state-of-the-art for investigation of the mechanisms related to blastinduced TBI, there are some limitations to their use.…”