Overview of Large Animal Models in SCI - Candace L. Floyd, Ph.D.
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Overview of Large Animal
Models in SCI
Candace L. Floyd, Ph.D.
Overview
• Epidemiology of spinal cord injury (SCI)
• Main research areas for advancement in care for persons with SCI
• Viewpoint on use of large animals as a translational intermediary
• Comparative anatomy examples of common large animal models of SCI
• Highlighting accomplishments in SCI research using large animal models
• Summary and recommendations on future use of large animal models in SCI
research
Definitions: Spinal Cord Injury
• Spinal cord injury (SCI): injury to the spinal cord resulting functional deficits
• Direct mechanical injury, followed by secondary injury process
• Functionally complete or incomplete injury… but spared tissue
MRI of Secondary Injury in Cervical SCI
Fracture Dislocation 48 hours 5 days 5 weeks
Injury
Sagittal MR images of acute and sub-acute SCI after a motor
vehicle accident
Source: Kulkarni et al., 1987, Neuroradiology 164: 837.
Epidemiology
Tetraplegia
• US Prevalence: ~291,000 Incomplete: 47%
Complete: 12%
• US Incidence: ~ 17,730 new cases
• Average age at injury: 43
• Main causes: Paraplegia:
Incomplete: 20%
Complete: 13%
Less than 1% of
persons
experience
complete
neurological
recovery at
Data from National SCI Statistical Center: Spinal Cord Injury hospital
Model Systems 2019 Fact Sheet discharge
Life Expectancy after SCI
Life Expectancy for Persons who survive the Firs 24 Hours
Motor Ventilator Leading causes
Age at Low Tetra High Tetra
No SCl Functional at Para Dependent
Injury (C5-C8) (C1-C4) of death are
any Level at any Level
septicemia,
20 yrs 60.6 52.6 45.5 40.1 33.7 11.2 and
40 yrs 41.7 35.0 29.6 24.8 20.8 8.8 pneumonia
60 yrs 24.1 19.3 15.9 13.1 11.1 3.7
Estimated Lifetime Costs by Age at Injury (health care and living costs)
Severity of Injury 25 years old 50 years old
High Tetraplegia (C1-C4) $5,010,748 $2,753,822
Data from National SCI
Low Tetraplegia (C5-C8) $3,661,165 $2,251,944 Statistical Center: Spinal Cord
Paraplegia $2,450,234 $1,608,015 Injury Model Systems 2019 Fact
Sheet
Incomplete Motor Functional at any
$1,674,012 $1,181,567
Level
Research Priorities
State of Care:
• Stabilization and Medical Management
• Acute and Chronic
• Rehabilitation services focuses on re-integration including
• Physical
• Psychological
• Social
• Physiatrists typically maintain long-term relationships with SCI
patient
• No “cure”: no treatment to robustly restore function
Health Concerns:
• Hand/arm Function
• Pressure Sore Management
• Bowl and Bladder Function
• Urinary tract infections
• Breathing and Cough
• Spasticity
• Neuropathic Pain
• Sexual Function Lo et al., 2016
• Effects of Aging Van Middendorp, et al. 2016
• Improved • New
translational pharmacology
models and clinical
management
Innovative
Discovery Tools Protection
CURE
Rehabilitation Repair &
& Retraining Regeneration
• Innovative
combinations of • Nanomaterials,
treatments HiFU and
pharmacology
Translation From Bench to Bedside is Challenging
• Success Rates in Pharmaceutic Research
• Average: 45% (Kola and Landis, 2014)
• Oncology: 5% (USFDA 2014 report)
• Neuroprotection in Stroke and TBI: 0%
• (over 50 clinical trials) Retxios, 2012
• Neuroprotection in SCI: ~1% (controversial)
• Interdisciplinary and active discussion on improving
translational research, worldwide
©UNIVERSITY OF UTAH HEALTH, 2017
Why Use Large Animal Models of Neurotrauma?
• More complex pathophysiology possible in large
animal models Focus on
• Rosenfeld et al., 2012; Vink, 2017 Porcine Models
• Anatomical differences between rodent and
human are reduced in large animal models
• Gyrencephalic brains
• Gray/white matter distributions
• Complex spinal circuity, particularly related to hand
function
Naturally
• Size, blood flow, and PK/PD Occurring IVDD
Fan and Lai, 2013
@UofU_MR #DaretoAchieve Physical Medicine & Rehabilitation
©UNIVERSITY OF UTAH HEALTH, 2017
SCI Experts and Patients Say…
• Rodent model is sufficient to proceed with a clinical
trial:
• Clinicians and Scientists: 54-75% DISAGREE
• Large animal model is necessary to proceed with a
clinical trial:
• Clinicians and Scientists: 65-77% AGREE
• Persons with SCI: 62-84% AGREE
Kwon et al., 2012, 2013
©UNIVERSITY OF UTAH HEALTH, 2017Kwon et al., 2015. Experimental Neurology 269:154-168
Method: Engaged members of the SCI research
community (41) in questionnaire and round-table
focus group
• 54% did not currently use large animal models
• Assessed large animal/ primate models of SCI
©UNIVERSITY OF UTAH HEALTH, 2017Highlighted Results from Kwon et al. 2015
62%
79%
80%
52%
68%
46%
©UNIVERSITY OF UTAH HEALTH, 2017Highlighted Results from Kwon et al. 2015
83%
78%
©UNIVERSITY OF UTAH HEALTH, 2017Key points from Kwon et al., 2015
• In general, large animal • Importantly, the
models are seen as a decision to use a large
necessary component animal model and
in the translational which model is best
research pipeline depends on the
research question to be
addressed
©UNIVERSITY OF UTAH HEALTH, 2017Gyrencephalic Brains & Biomechanical Parameters
Species Brain Wt (g) Gyrification
Index
Human 1400 2.51
Rhesus monkey 90 0.91
Rat: Uniform stress fields Human: Maximum stress fields at
base of sulci Domestic pig 95.3 2.16
In angular acceleration, sulci focus the Rat 2.48 0.02
maximal stress field to the base of the sulcus Mouse 0.65 0.03
Pillay & Manger, 2007
Vink et al., 2017 Dog (Beagle) 6.9 1.59
W
Wosinski et al. 1996
©UNIVERSITY OF UTAH HEALTH, 2017Spinal Cord Anatomy affecting SCI
©UNIVERSITY OF UTAH HEALTH, 2017RAT
Bilgen et al., 2006
PIG
HUMAN
Leonard et al., 2017
©UNIVERSITY OF UTAH HEALTH, 2017Complex motor circuity in primates • Direct vs. indirect pathways from motor cortex controlling hand function (Isa et al., 2013) • Mono-synaptic vs. poly-synaptic or oligosynaptic circuity affects function, plasticity, and repair strategies • Mono-synaptic cortico-motoneuronal connexion underlies dexterous finger movement and is unique to primates (Pettersson et al., 2007)
Success in Progress: Schwann cell transplantation
Human
Rat
Pig
©UNIVERSITY OF UTAH HEALTH, 2017Directly measuring variables related to spinal cord
perfusion and blood flow after SCI
Observed an imbalance between spinal
cord blood flow and tissue metabolism,
suggesting on-going hypoxia/ischemia
©UNIVERSITY OF UTAH HEALTH, 2017Summary and Recommendations
Summary: Recommendation:
• SCI remains an area of • The selection of the
great need for research, species for large animal
with many gaps research is based on the
remaining research question and
the justification for the
• Large animal models are use of the model should
considered by SCI be a key component in
research experts and the consideration of the
patients to be a merit of the research
necessary tool in application
discovery and translation
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