Animal models of traumatic brain injury Flashcards
Primitive level: steps of TBI?
mechanical input -> primary injury -> secondary injuries ->
secondary injuries and restorative processes influence ong term outcome
Describe impact effects of primary injury?
- tissue deformation
- contusions
- lacerations
- haemorrhages
Describe non-impact effects of primary injury?
- diffuse axonal injury (DAI)
- swelling
Examples of focal injury?
- contusions
- lacerations
- haemorrhages
Examples of diffuse injury?
- DAI
- swelling/herniation
- ischaemia
- vascular injury
Describe the mechanisms behind secondary injury in TBI
Primary injury -> Ca2+ influx -> NT release -> excitotoxicity
-> mitochondrial damage -> ROS -> gene exp -> BBB opening -> inflammation -> oedema -> raised ICP -> herniation
Inflammation -> release of DAMPs, chemokines, cytokines -> neutrophils, monocytes -> microglia/astrocytes
Why are in vivo models of TBI necessary?
Single models can’t truly reproduce the complex pathophysiological spectrym of TBI
(need to ID mechanisms and test therapies)
How to assess the validity of a model?
- face validity: same phenomenology
- construct validity: similar underlying mechanisms
- aetiological validity: similar changes in aetiology
- predictive validity: predictive value, accuracy and reliability
List similarities between mammalian TBI models and real TBI
- gross histopathology (contusion, BBB disruption, cell loss, brain atrophy)
- molecular changes (inflammation/apoptosis/oxidative stress/axonal injury)
- functional deficits (memory and learning deficits)
- long term effects (detectable in rodents up to 1 yr)
Differences between primary mammalian TBI models and real TBI
Anaesthesia (not in human TBI): type of anaesthesia used can affect functional and histological outcome e.g. diff. cell count
Craniotomy (not in human TBI): surgery is a brain injury itself; MRI shows craniotomy results in oedema/inflammation
Primary problems of in vivo TBI models
- Drug selection: drugs rushed to trials (e.g. CRASH study gave steroids for TBI for anti-inflamm but this increased mortality)
- Trial design: low participant number, single vs multi-centre trials
- Patient selection: mild/mod/severe TBI, confounding factors, sex?
- Endpoints: GCS, motor/cognitive impairments, survival
Describe and evaluate in vitro TBI models
Use
- immortalised cell lines
- primary cell cultures
- organtypic slices
- acute explants
- 3D organoids
Induce TBI through:
- stretch
- shearing
- weight drop
- blast injury
- stir, transection, acceleration
PROS
- repeatable
- controlled biomechanics
- environmental and pathophysiological isolation
- high throught + screening approaches
CONS
- snapshot
- clinical improvement?
- functional outcome?
- network effects?
- extra-CNS effects?
List examples of in vivo TBI models
- drosophilia (invertebrates)
- zebrafish (non-mammalian)
MAMMALIAN:
- controlled cortical impact
- fluid percussion
- weight drop
- penetrating ballistic model
- blast injury
- rotational model
- Maryland model
Describe and evaluate drosophilia (invertebrate) model method
- inside container w/ loaded spring to fling them -> TBI
- pipette pressure pulse to hit head
Causes vacuoles and cell loss
PROS
- cheap
- no ethical restrictions
- fast life cycle
- easy genetic modification
CONS
- reproducibility
- no skull
- different biomechanics
- morphological differences
Describe and evaluate zebrafish (non-mammalian) model method
- stab wound injury
- weight drop
- focussed ultrasound
Causes inflammation, cell loss, delta (behaviour)
PROS
- fast life cycle
- less ethical restrictions
- study behaviour
- vertebrate
CONS
- reproducibility
- different biomechanics
- different metabolism
Describe and evaluate controlled cortical impact TBI method
Impactor accelerated to hit brain without affecting the skull -> focal contusion
Damage depends on speed and depth of injury
PROS
- highly reproducilbe
- biomechanical control
- species scalability
- low mortality
- age-effects
CONS
- craniotomy required (affecting results)
- contusion not always a feature of clinical TBI
- anaesthesia could affect outcome
Describe and evaluate fluid percussion as a TBI model
Fluid pressure wave hits brain -> mixed focal contusion and diffuse injury
Damage depends on amount of pressure
PROS
- highly reproducible
- biomechanical control
- species scalability
- age-effects
CONS
- craniotomy required (could affect results)
- high mortality
Describe and evaluate weight drop models for TBI
Free falling guided weight hits either exposed dura/exposed skull/steel disc/skull
PROS
- closed head model
- easy operation
CONS
- reproducibility
- craniotomy required
- high mortality
Describe and evaluate penetrating ballistic model in TBI
Air-rifle pellets/probes mimic penetrating brain injury (shockwave or temporary cavity)
PROS
- similar biomechanics to clinical penetrating TBI
- species scalability
CONS
- reproducibility
- bone fragments in skull
- rare clinically
Describe and evaluate blast injury model for TBI
Shock tube/open field explosions mimic blast wave, rotational effects + heat/gas/smoke
PROS
- similar biomechanics
- species scalability
CONS
- reproducibility
- rare clinically
Describe rotational model for TBI
Dart shot to rotate head to create whiplash
Describe Maryland model for TBI
Steel balls hit metal component on head
Models frontal injury and coup-countre coup
Illustrate the process of preclinical to clinical translation using TBI models as
example
E.g. progesterone
Pre-clinical TBI studies: progesterone had beneficial effects
Phase II: beneficial effects
Multi-centre study: adverse effects
WHY?
- different application route (intraperitoneal pre-clin VS oral/iv clinical)
- suboptimal endpoints
- few dose-response studies in animals
