Traumatic brain injury (TBI) poses a major public health issue, costing over $76 billion annually in the US. While current management focuses on reducing secondary brain damage, cell-based therapy shows promise as an emerging treatment. Animal and early phase human trials have shown cell therapies using mesenchymal stem cells, neural progenitor cells, and bone marrow-derived cells can improve motor function, learning ability, and reduce inflammation following TBI. However, more research is still needed to determine the optimal cell type, route of delivery, timing of treatment, and safety monitoring methods to fully understand and maximize the therapeutic potential of cell-based therapies for TBI.

1. Dr. Malaka Munasinghe
Registrar in Anaesthesia
2015.09.17

2. Significance!!!
USA stats by 2010
-2 million visits to ETU
- 0.3 million admissions
- 55,000 deaths ( 30% of all injury related deaths)
- COST
76 BILLION DOLLARS

3. Current lines of Management
-supportive
- Focus on,
reducing secondary brain damage
- No effective definitive therapy
BUT - EMERGING
CELL BASED THERAPY

4. Pathophysioloy of TBI
Mechanism
-Direct impact
- Acceleration and deceleration/ rotational forces
- Primary phase
- Secondary phase

5. Primary phase
-immediate
- Massive neuronal depolarization
Release of neurotransmitters
- monocyte/macrophage mediated phagocytosis
- Complement mediated cytolysis
- Diffuse neuronal dysfunction

6. - disrupted blood brain barrier
- Expressed GLUT-1
- Synthesis and release of NO
cerebral vasodilatation
ICP
Worsen primary brain injury

7. Secondary phase
- Few hours after TBI
- Last several days
- Intracellular Ca2+ influx
- Free radical formation and lipid peroxidation
- Mitochondrial dysfunction
-Neuronal apoptosis ( focal and diffuse)
hippocampus- more vulnerable

8. - Upregulation of NGF/BDNF
- Downregulation of neutrophin-3 advantageous
BUT,
- NOT EFFECTIVE for Endogenous stem cell function
In repairing
AS,
Acute inflammatory enviorenment after TBI
( May last several weeks)

9. CELL BASED THERAPY FOR TBI
Cell types used
 Mesenchymal stem cells(MSC)
 Neural progenitor cells(NPC)
 Ntera 2(NT2) cells
 Embryonic stem cells
 Multipotent adult progenitor cells
 Endothelial progenitor cells

10. Mechanisms of action of cell based therapy
 Differentiaton in to locoregional cells
 Reduction of oedema and inflammation in TBI
 Secretion of chemokine and growth factors
 Enhancing neurogenesis,angiogenesis and
vasculogenesis
 Stabilizing damaged cells by gene and protein
transfer (fusion or intercellular contact)
 Enhancing migration of host neurogenic cells to the
area of TBI

11. Delivery of cells
 Intravenous
 Lateral ventricle
 Internal carotid artery
 Stereotactic method

12. Scaffolds used for cell delivery
 Fibrin
 Matrigel
 Collagen
 Gelatin
( provides an extracellular matrix
Maintain viability)

13. Timing of delivery of cells
 Just after the TBI to one week after
 No study analysing effectiveness in different timings
 BUT-
even with late administrations- improvement +

14. Assessment of improvement(ANIMAL MODELS)
 Motor function ; stepping or balance beam tests
 Learning ability ; morris walter maze test
 Reduction in cerebral lesion volume
- histology
- MRI/PET
 Reduced proinflammatory cytokines(IL1/6/TNF α)

15. CURRENT CLINICAL TRIALS
 Cox and colleagues- 2011
- prospective, non-random ,open label, phase 1/2
trial
- 1O chlidren aged 5-14 years with post resuscitation
GCS-58
- Autologus bone marrow derived cells
- administered 48 hrs later/followed up to 6 months
- three patients –complete recovery

16. Cox and colleagues- 2011 ctd…
BUT
ALL- SOME NEUROLOGICAL IMPROVEMENT!!!
-No post injury seizures
- No refractory intracranial pressure
-No new ischemic events
- No alteration in CPP

17. Tian and colleagues 2013…
- prospective, non-random ,open label, phase 1/2
trial
- 97 patients in subacute phase of TBI
- Intrathecal administration of autologus bone marrow
derived cells 02months after the injury
- Followed up for 40 days
- ¼-improved motor functions
- 11 out of 24 patients in vegetative state- improved
consciousness

18. Ongoing trials +++
One- to determine optimal route for delivery of cells

19. Concerns….
- Optimal route and timing yet to be deciced
- Stereotactic administration- invasive/need a
neurosurgeon
- Monitoring parameters to assess safety and efficacy
options - MRI to assess cerebral perfusion+ lesion
- concnt. of systemic pro and anti
inflammatory markers
- comprehensive neurological testing
- assessing functional recovery of
hippocampus

20. - gnerating,processing ,storage of stem/progenitor
cells- costly
- Difficulty in differentiating iatrogenic tumour foci
from inflamed tissue

21. Summary
- Traumatic brain injury is a major public health issue
- Cell based therapy would be a promising approach
- Animal and phase 1/2 human trials have shown
positive results
- Though, more studies are needed in understanding
the therapeutic mechanisms of stem cell therapy.

22.  References
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23. THANK YOU….