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.
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.
Pritchard
Christopher D
CD
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. cpritcha@mit.edu
Slotkin
Jonathan R
JR
Yu
Dou
D
Dai
Haining
H
Lawrence
Matthew S
MS
Bronson
Roderick T
RT
Reynolds
Francis M
FM
Teng
Yang D
YD
Woodard
Eric J
EJ
Langer
Robert S
RS
D020341:Absorbable Implants; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002522:Chlorocebus aethiops / Q000033:anatomy & histology / Q000502:physiology* / Q000601:surgery*; D004195:Disease Models, Animal; D006085:Graft Survival / Q000502:physiology; D006801:Humans; D008297:Male; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology; D019635:Neurosurgical Procedures / Q000379:methods; D019919:Prosthesis Implantation / Q000379:methods; D020127:Recovery of Function / Q000502:physiology; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D054457:Tissue Scaffolds; D016896:Treatment Outcome