In Vitro Models of Traumatic Brain Injury

Morrison, Barclay; Elkin, Benjamin S.; Dollé, Jean-Pierre; Yarmush, Martin L.

doi:10.1146/annurev-bioeng-071910-124706

Cited by 210 publications

(182 citation statements)

References 205 publications

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“…loss of action potentials) but also functional response such as synaptic and white matter plasticity, and long term potentiation and depression 28,[55][56] . In vitro brain slice and the recently emerging organ-on-chip and human-on-chip technologies [57][58][59] provide foundation for the development of 'living', 'humanised' brain-on-chip devices that could be used to investigate various primary and secondary injury mechanisms but also responses to treatments such as hypothermia, electro/magnetic stimulation and pharmacological interventions. Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Experimental in vitro and animal models of TBI have shown that the primary microdamage to various neuro-structures initiates a cascade of biophysical and neurochemical events, lasting from minutes to hours, resulting in either axonal, synaptic and vascular repair or permanent damage [59][60] . Development of secondary injury models involves construction of a conceptual mechanistic model of injury mechanisms, mathematical formulation of the underlying mechano-biology model and calibration/ validation of the model on available in vitro experimental data.…”

Section: Discussionmentioning

confidence: 99%

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Multiscale Modelling of Blast-Induced TBI Mechanobiology - From Body to Neuron to Molecule

et al. 2017

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Blast induced traumatic brain injury (bTBI) has become a signature wound of the recent military operations and is becoming a significant factor of recent civilian blast explosion events. In spite of significant clinical and preclinical research on TBI, current understanding of injury mechanisms is limited and little is known about the short-term and long-term outcomes. Mathematical models of bTBI may provide capabilities to study brain injury mechanisms, perhaps accelerate the development of neuroprotective strategies and aid in the development of improved personal protective equipment. The paper presents a novel multiscale simulation framework that couples the body/brain scale biomechanics with micro-scale mechanobiology to study the effects of 'primary' micro-damage to neuro-axonal structures with the 'secondary' injury and repair mechanisms. Our results show that oligodendrocyte myelinating processes distribute strains among neighbour axons and cause their off-axis deformations. Similar effects have been observed at the finer scale for the Tau-Microtubule interaction. The need for coupled modelling of primary injury biomechanics, secondary injury mechanobiology and model based assessment of injury severity scores is discussed. A novel integrated computational and experimental approach is described coupling micro-scale injury criteria for the primary micro-mechanical damage to brain tissue/cells as well as to investigate various secondary injury mechanisms.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Multiscale Modelling of Blast-Induced TBI Mechanobiology - From Body to Neuron to Molecule

et al. 2017

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“…advantageous complements when it comes to exploration of isolated phenomena. Moreover, in vitro models are easy to use, affordable, less ethically challenged, reproducible and better controlled, and re present a good platform for drug screening (21)(22)(23). Hence, in vitro models of TBI are a variable tool in studying the pathobiology beyond brain injury and there is a need to define them more profoundly.…”

Section: Discussionmentioning

confidence: 99%

“…A number of in vitro models have been introduced in order to reproduce the features of interest in an isolated system and to allow manipulations, monitoring on multiple levels in real time, while being precisely controlled (11,12). One of such is a scratchwound assay (SW), first established as a simple, reproducible assay for the analysis of cell migration in vitro (13).…”

Section: Kratak Sadr`ajmentioning

confidence: 99%

Real-Time PCR and Immunocytochemical Study of Chondroitin Sulfate Proteoglycans after Scratch Wounding in Cultured Astrocytes / PCR I IMUNOCITOHEMIJSKA STUDIJA EKSPRESIJE HONDROITIN-SULFATNIH PROTEOGLIKANA NAKON POVREDE ASTROCITA U KULTURI

Parabucki¹,

Santrač²,

Savić³

et al. 2013

Journal of Medical Biochemistry

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SummaryBackground: Various in vivo and in vitro models have been described in order to elucidate the pathobiology underlying the traumatic brain injury (TBI) and test potentially suitable treatments. Since TBI is a complex disease, models differ in regard to the aspect of TBI that is being investigated. One of the used in vitro models is the scratch wound assay, first established as a reproducible, low-cost assay for the analysis of cell migration in vitro. The aim of the present study was to further investigate the relevancy of this model as a counterpart of in vivo TBI models. Methods: We have examined the astrocytic response to a mechanical injury in terms of expression of chondroitin sulfate proteoglycans (CSPGs) -phosphacan, neurocan and brevican, using real-time PCR and immunocytochemistry. Results: Our results indicate that in vitro scratch wounding alters the expression profile of examined CSPGs. Four hours after the scratch injury of the astrocytic monolayer, real-time PCR analysis revealed upregulation of mRNA levels for phosphacan (3-fold) and neurocan (2-fold), whereas brevican mRNA was downregulated (2-fold). Immunofluorescent signal for phosphacan and neurocan was more intense in astrocytes close to the injury site, while brevican was scarcely present in cultured astrocytes. Conclusions: Obtained results indicate that CSPGs are differentially expressed by astrocytes after scratch wounding,

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“…Numerous studies show that even mild concussions, if induced repeatedly, can lead to permanent brain damage; the issue is constantly debated in the sports media, but especially in football [17]. The pathophysiology of TBI is heterogeneous [18,19,16]. However, all severities of TBI trigger axonal damage widespread over a large number of neurons [20].…”

Section: Introductionmentioning

confidence: 99%

Cognitive and behavioral deficits arising from neurodegeneration and traumatic brain injury: a model for the underlying role of focal axonal swellings in neuronal networks with plasticity

Rudy¹,

Maia²,

Kutz³

2016

J Integr Syst Neurosci

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Neurodegenerative diseases and traumatic brain injury, whose hallmark features are the presence of focal axonal swellings (FAS), are leading causes of cognitive dysfunction. By leveraging biophysical observations of FAS statistics, we develop a theoretical model of functional neural network activity driven by adaptive changes from plasticity. Based upon the FORCE model of Sussillo and Abbott [1], our innovations highlight the role of plasticity in overcoming injuries and degeneration of neurons in a network architecture. We provide a quantitative measure, on a network level, of cognitive deficits arising from injury. We demonstrate that plasticity is capable of overcoming mild injuries while failing to compensate for more severe injuries. Such injuries are characterized by their underlying effect on spike trains propagating through the neurons in a network architecture. Specifically, spike trains can be filtered in firing rate, or blocked under more severe FAS. The level of injury dictates the FORCE model's ability to produce a desired output functionality (and associated behavior) and allows for quantitative metrics for accessing cognitive and behavioral deficits. Thus a direct link between FAS in neural networks and compromised functional response can be established. The theoretical framework developed is a promising computational framework for providing a deeper understanding of the cognitive deficits arising in, for instance, Alzheimer's, Parkinson's, Multiple-Sclerosis, and TBI.

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In Vitro Models of Traumatic Brain Injury

Cited by 210 publications

References 205 publications

Multiscale Modelling of Blast-Induced TBI Mechanobiology - From Body to Neuron to Molecule

Multiscale Modelling of Blast-Induced TBI Mechanobiology - From Body to Neuron to Molecule

Real-Time PCR and Immunocytochemical Study of Chondroitin Sulfate Proteoglycans after Scratch Wounding in Cultured Astrocytes / PCR I IMUNOCITOHEMIJSKA STUDIJA EKSPRESIJE HONDROITIN-SULFATNIH PROTEOGLIKANA NAKON POVREDE ASTROCITA U KULTURI

Cognitive and behavioral deficits arising from neurodegeneration and traumatic brain injury: a model for the underlying role of focal axonal swellings in neuronal networks with plasticity

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