Animal Models of Traumatic Brain Injury Flashcards
Describe the basics of TBI biomechanics and pathophysiology Critically evaluate the major differences between in vivo and in vitro models Describe the primary mammalian TBI models and discuss their differences Critically evaluate the primary problems of in vivo TBI models Understand why in vivo TBI models are necessary Illustrate the process of preclinical to clinical translation using TBI models
Which groups are most at risk of TBI-related death?
Children under 4 and adults over 75
What causes the primary injury in TBI?
A mechanical input as the direct result of the transfer of energy
How does TBI lead to secondary and progressive injuries?
TBI causes an influx of calcium, leading to mitochondrial damage and free radical release. This activates upstream signalling mechanisms and gene expression
Name the three types of force that can be experienced in a TBI
Linear, rotational, or angular
Describe the difference between contact effects and inertial effects
Contact effects lead to tissue deformation and a focal injury, such as a contusion, laceration, or haemorrhage. Inertial effects lead to shearing and tearing, with injury - such as diffuse axonal injury or swelling - occurring anywhere in the brain;
Give 4 potential explanations for past clinical trial failure in TBI
Rush to clinical trials with insufficient animal data, poor trial design, patient selection (too many confounders), and endpoint selection
Name 3 requirements which TBI clinical trials must fulfill
1) Appropriate target identification, allowing proper drug selection
2) Disease monitoring for long-term effects
3) Outcome evaluation with an appropriate choice of endpoint
State the 4 concepts models must follow in order to be valid
1) Face validity - same phenomenology as human TBI
2) Construct validity - similar underlying mechanisms
3) Aetiological validity - similar changes in aetiology
4) Predictive validity and reliability
What are in vitro models of TBI useful for studying?
Single isolated factors, such as biomechanics, excitotoxicity, and apoptosis
Give at least 3 advantages of in vitro models of TBI
Repeatable, controlled biomechanics, environmental and pathophysiological isolation, high throughput and screening approaches possible
Give at least 3 disadvantages of in vitro models of TBI
Snapshot of a dynamic process, clinical improvement cannot be assessed, does not account for extra-CNS effects
Give at least 3 examples of in vitro models of TBI
Immortalised cell lines, primary neuronal or glial cultures, organotypic slices, resected human CNS tissue, 3D cultures (organoids)
Give an example of an in vitro model of rotational strain
Stir-bar injury, which models pressure
Give an example of an in vitro model of a focal skull contact injury
Weight drop, which models tissue compression
Give at least 3 advantages of Drosophila as a model of TBI
No ethical restrictions, cheap maintenance, fast life cycle for large-scale and long-term studies, easy genetic modifications
Give at least 3 disadvantages of Drosophila as a model of TBI
Differences in morphology and metabolism, no skull, limited behavioural tests, biomechanics, poor reproducibility
Give at least 3 advantages of zebrafish as a model of TBI
Fewer ethical restrictions, vertebrate unlike Drosophila, cheap maintenance, fast life cycle, behavioural effects can be seen, can use weight drop injury or focused US injury
Give at least 3 disadvantages of zebrafish as a model of TBI
Different metabolism, different biomechanics, poor reproducibility
Name the main 5 mammalian animal models of TBI, and the injury they model
Weight drop - diffuse or focal injury
Controlled cortical impact - focal injury
Fluid percussion - diffuse and focal injury
Penetrating ballistic-like injury - focal injury
Blast - diffuse injury
Give 3 examples of focal injuries
Contusions, lacerations, haemorrhages
Give at least 3 examples of diffuse injuries
Diffuse axonal injury, swelling, ischaemia, vascular injury
State at least 3 gross histopathological changes in TBI in animal models confirmed in humans
Cortical contusion, blood-brain barrier disruption, hippocampal cell loss, brain atrophy
State at least 3 molecular changes in TBI in animal models confirmed in humans
Inflammation, apoptosis and autophagy, oxidative stress, axonal injury, blood flow
State 3 functional deficits in TBI in animal models confirmed in humans
Memory and learning deficits, motor deficits, emotional deficits
Describe the weight drop model of TBI
A falling, guided weight hits either the exposed skull, exposed skull with a steel disc, or just the exposed dura, to mimic mixed injuries, diffuse injuries, or focal injuries respectively
Describe the controlled cortical impact model of TBI
A pneumatic or electromagnetic impactor directly transfers kinetic energy through a rigid impactor. Electromagnetic impactors can be used at higher velocity and are smaller, with typically more reproducible results
Give at least 3 disadvantages of the controlled cortical impact model of TBI
Complex instrument, pneumatic impactors prone to wear, craniotomy necessary, pronounced tissue loss possible, limited diffuse injury, contusion not always a feature of clinical TBI
Describe the lateral fluid percussion model of TBI, and state which animals it is used in
Fluidic pressure waves - produced by pendulum devices or pneumatically driven devices - impact on and compress the dura mater and tissue, causing focal cortical contusion and diffuse injury. It is used in cats and rabbits
Describe the lateral fluid percussion model of TBI, and state which animals it is used in
Fluidic pressure waves - produced by pendulum devices or pneumatically driven devices - impact on and compress the dura mater and tissue, causing focal cortical contusion and diffuse injury
Give at least 3 advantages of the lateral fluid percussion model of TBI
Highly reproducible, pressure pulse determines severity, good for modelling axonal and diffuse injury, species scalability, can assess age effects
Give at least 3 disadvantages of the lateral fluid percussion model of TBI
Craniotomy necessary, higher mortality, brainstem and ventricular involvement
Describe the penetrating ballistic-like injury model of TBI
A projectile - usually air rifle pellets - penetrates into the brain. At high velocity this mimics bullet injuries, and at low velocity knife wounds
Give an advantage of the penetrating ballistic-like injury model of TBI
Very similar biomechanics to penetrating TBI
Give at least 3 disadvantages of the penetrating ballistic-like injury model of TBI
Craniotomy may be necessary, bone fragments from skull can confound experiments, clinically less often seen outside of conflict zones and the US, less reproducible
Describe the blast injury model of TBI
A shock tube is used to direct a blast wave from either compressed air or detonation. This models secondary and impact rotational loading of the brain, producing diffuse axonal injury, diffuse oedema, and significant peripheral effects
Give an advantage of the blast injury model of TBI
Similar biomechanics to human blast TBI
Give 2 disadvantages of the blast injury model of TBI
Clinically less often seen, less reproducible
Give 3 general problems with the use of animal models
Reproducibility less than 50%, enormously expensive, often not enough randomisation, blinding, or power calculations
Give 2 specific problems with the use of animal models for TBI
Anaesthesia affects the functional and histopathological outcome, and craniotomy is a brain injury itself - causing lesions, functional deficits, and inflammation - so confounds results
