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
