TY - JOUR
T1 - Establishing a model spinal cord injury in the African green monkey for the preclinical evaluation of biodegradable polymer scaffolds seeded with human neural stem cells
AU - Pritchard, Christopher D.
AU - Slotkin, Jonathan R.
AU - Yu, Dou
AU - Dai, Haining
AU - Lawrence, Matthew S.
AU - Bronson, Roderick T.
AU - Reynolds, Francis M.
AU - Teng, Yang D.
AU - Woodard, Eric J.
AU - Langer, Robert S.
N1 - Funding Information:
Human neural stem cells generated and provided by Evan Y. Snyder (Burnham Institute for Medical Research, La Jolla, CA, [email protected] ). We thank William L. Neeley for assistance with PLGA scaffold fabrication (MIT, Cambridge, MA), Darcy Benedict for assistance with cell culture and seeding (Brigham and Women's Hospital, Boston, MA) and Dr. D. Eugene Redmond Jr. for assistance with surgical procedures and animal care (St. Kitts Biomedical Research Foundation, St. Kitts and Nevis). We thank Robert C. Switzer III for assistance with staining protocols (NeuroScience Associates, Knoxville, TN). We thank George Calapai for video editing, Lauren Mitarotondo for writing assistance and Janice Ye for image analysis (InVivo Therapeutics, Cambridge, MA). C.D.P. was supported by the MIT/CIMIT Medical Engineering Fellowship . InVivo Therapeutics thanks its investors and advisors for support. This study was funded by InVivo Therapeutics Corporation .
PY - 2010/5
Y1 - 2010/5
N2 - Given the involvement of post-mitotic neurons, long axonal tracts and incompletely elucidated injury and repair pathways, spinal cord injury (SCI) presents a particular challenge for the creation of preclinical models to robustly evaluate longitudinal changes in neuromotor function in the setting in the presence and absence of intervention. While rodent models exhibit high degrees of spontaneous recovery from SCI injury, animal care concerns preclude complete cord transections in non-human primates and other larger vertebrate models. To overcome such limitations a segmental thoracic (T9-T10) spinal cord hemisection was created and characterized in the African green monkey. Physiological tolerance of the model permitted behavioral analyses for a prolonged period post-injury, extending to predefined study termination points at which histological and immunohistochemical analyses were performed. Four monkeys were evaluated (one receiving no implant at the lesion site, one receiving a poly(lactide-co-glycolide) (PLGA) scaffold, and two receiving PLGA scaffolds seeded with human neural stem cells (hNSC)). All subjects exhibited Brown-Séquard syndrome 2 days post-injury consisting of ipsilateral hindlimb paralysis and contralateral hindlimb hypesthesia with preservation of bowel and bladder function. A 20-point observational behavioral scoring system allowed quantitative characterization of the levels of functional recovery. Histological endpoints including silver degenerative staining and Iba1 immunohistochemistry, for microglial and macrophage activation, were determined to reliably define lesion extent and correlate with neurobehavioral data, and justify invasive telemetered electromyographic and kinematic studies to more definitively address efficacy and mechanism.
AB - Given the involvement of post-mitotic neurons, long axonal tracts and incompletely elucidated injury and repair pathways, spinal cord injury (SCI) presents a particular challenge for the creation of preclinical models to robustly evaluate longitudinal changes in neuromotor function in the setting in the presence and absence of intervention. While rodent models exhibit high degrees of spontaneous recovery from SCI injury, animal care concerns preclude complete cord transections in non-human primates and other larger vertebrate models. To overcome such limitations a segmental thoracic (T9-T10) spinal cord hemisection was created and characterized in the African green monkey. Physiological tolerance of the model permitted behavioral analyses for a prolonged period post-injury, extending to predefined study termination points at which histological and immunohistochemical analyses were performed. Four monkeys were evaluated (one receiving no implant at the lesion site, one receiving a poly(lactide-co-glycolide) (PLGA) scaffold, and two receiving PLGA scaffolds seeded with human neural stem cells (hNSC)). All subjects exhibited Brown-Séquard syndrome 2 days post-injury consisting of ipsilateral hindlimb paralysis and contralateral hindlimb hypesthesia with preservation of bowel and bladder function. A 20-point observational behavioral scoring system allowed quantitative characterization of the levels of functional recovery. Histological endpoints including silver degenerative staining and Iba1 immunohistochemistry, for microglial and macrophage activation, were determined to reliably define lesion extent and correlate with neurobehavioral data, and justify invasive telemetered electromyographic and kinematic studies to more definitively address efficacy and mechanism.
KW - African green monkey
KW - Behavioral scoring
KW - Biomaterials
KW - Injury model
KW - Non-human primate
KW - Spinal cord injury
KW - Stem cells
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U2 - 10.1016/j.jneumeth.2010.02.019
DO - 10.1016/j.jneumeth.2010.02.019
M3 - Article
C2 - 20219534
AN - SCOPUS:77951175537
SN - 0165-0270
VL - 188
SP - 258
EP - 269
JO - Journal of Neuroscience Methods
JF - Journal of Neuroscience Methods
IS - 2
ER -