traumatic brain injury

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In Vitro Models as a Platform to Investigate Traumatic Brain Injury

Ashwin Kumaria

Traumatic Brain Injury (TBI) remains a significant cause of mortality and morbidity, affecting individuals of all age groups. Much remains to be learned about its complex pathophysiology, with a view to designing effective neuroprotective strategies to protect sublethally injured brain tissue that would otherwise die in secondary injury processes. Experimental in vivo models offer the potential to study TBI in the laboratory, however, treatments that were neuroprotective in animals have, thus far, largely failed to translate in human clinical studies. In vitro models of neurotrauma can be used to study specific pathophysiological cascades — individually and without confounding factors — and to test potential neuroprotective strategies. These in vitro models include transection, compression, barotrauma, acceleration, hydrodynamic, chemical injury and cell-stretch methodologies. Various cell culture systems can also be utilised, including brain-on-a-chip, immortalised cell lines, primary cultures, acute preparations and organotypic cultures. Potential positive outcomes of the increased use of in vitro platforms to study TBI would be the refinement of in vivo experiments, as well as enhanced translation of the results into clinically meaningful neuroprotective strategies for the future. In addition, the replacement of in vivo experiments by suitable in vitro studies would lead to a welcome reduction in the numbers of animal procedures in this ethically-challenging field.

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Comment – A Critical Review of Anaesthetised Animal Models and Alternatives for Military Research, Testing and Training, with a Focus on Blast Damage, Haemorrhage and Resuscitation

Robert D. Combes

Military research, testing, and surgical and resuscitation training, are aimed at mitigating the consequences of warfare and terrorism to armed forces and civilians. Traumatisation and tissue damage due to explosions, and acute loss of blood due to haemorrhage, remain crucial, potentially preventable, causes of battlefield casualties and mortalities. There is also the additional threat from inhalation of chemical and aerosolised biological weapons. The use of anaesthetised animal models, and their respective replacement alternatives, for military purposes — particularly for blast injury, haemorrhaging and resuscitation training — is critically reviewed. Scientific problems with the animal models include the use of crude, uncontrolled and non-standardised methods for traumatisation, an inability to model all key trauma mechanisms, and complex modulating effects of general anaesthesia on target organ physiology. Such effects depend on the anaesthetic and influence the cardiovascular system, respiration, breathing, cerebral haemodynamics, neuroprotection, and the integrity of the blood–brain barrier. Some anaesthetics also bind to the NMDA brain receptor with possible differential consequences in control and anaesthetised animals. There is also some evidence for gender-specific effects. Despite the fact that these issues are widely known, there is little published information on their potential, at best, to complicate data interpretation and, at worst, to invalidate animal models. There is also a paucity of detail on the anaesthesiology used in studies, and this can hinder correct data evaluation. Welfare issues relate mainly to the possibility of acute pain as a side-effect of traumatisation in recovered animals. Moreover, there is the increased potential for animals to suffer when anaesthesia is temporary, and the procedures invasive. These dilemmas can be addressed, however, as a diverse range of replacement approaches exist, including computer and mathematical dynamic modelling of the human body, cadavers, interactive human patient simulators for training, in vitro techniques involving organotypic cultures of target organs, and epidemiological and clinical studies. While the first four of these have long proven useful for developing protective measures and predicting the consequences of trauma, and although many phenomena and their sequelae arising from different forms of trauma in vivo can be induced and reproduced in vitro, non-animal approaches require further development, and their validation and use need to be coordinated and harmonised. Recommendations to these ends are proposed, and the scientific and welfare problems associated with animal models are addressed, with the future focus being on the use of batteries of complementary replacement methods deployed in integrated strategies, and on greater transparency and scientific cooperation.

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