title: A controlled spinal cord contusion for the rhesus macaque monkey.
abstract: Most in vivo spinal cord injury (SCI) experimental models use rodents. Due to the anatomical and functional differences between rodents and humans, reliable large animal models, such as non-human primates, of SCI are critically needed to facilitate translation of laboratory discoveries to clinical applications. Here we report the establishment of a controlled spinal contusion model that produces severity-dependent functional and histological deficits in non-human primates. Six adult male rhesus macaque monkeys underwent mild to moderate contusive SCI using 1.0 and 1.5mm tissue displacement injuries at T9 or sham laminectomy (n=2/group). Multiple assessments including motor-evoked potential (MEP), somatosensory-evoked potential (SSEP), MR imaging, and monkey hindlimb score (MHS) were performed. Monkeys were sacrificed at 6 months post-injury, and the lesion area was examined for cavitation, axons, myelin, and astrocytic responses. The MHS demonstrated that both the 1.0 and 1.5mm displacement injuries created discriminative neurological deficits which were severity-dependent. The MEP response rate was depressed after a 1.0mm injury and was abolished after a 1.5mm injury. The SSEP response rate was slightly decreased following both the 1.0 and 1.5mm SCI. MRI imaging demonstrated an increase in T2 signal at the lesion site at 3 and 6months, and diffusion tensor imaging (DTI) tractography showed interrupted fiber tracts at the lesion site at 4h and at 6 months post-SCI. Histologically, severity-dependent spinal cord atrophy, axonal degeneration, and myelin loss were found after both injury severities. Notably, strong astrocytic gliosis was not observed at the lesion penumbra in the monkey. In summary, we describe the development of a clinically-relevant contusive SCI model that produces severity-dependent anatomical and functional deficits in non-human primates. Such a model may advance the translation of novel SCI repair strategies to the clinic.
authors.affiliation: Department of Laboratory Animal Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
authors.forename: Zhengwen
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Norton Neuroscience Institute, Norton Healthcare, Louisville, KY 40202, USA.
authors.forename: Yi Ping
authors.initials: YP
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Animal Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Laboratory Animal Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
authors.forename: Guofeng
authors.initials: G
authors.lastname: Yan
authors.affiliation: Department of Laboratory Animal Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Norton Neuroscience Institute, Norton Healthcare, Louisville, KY 40202, USA.
authors.forename: Lisa B E
authors.initials: LBE
authors.lastname: Shields
authors.affiliation: Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Walker
authors.affiliation: Department of Radiology, Ruijing Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
authors.forename: Kemin
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Radiology, Ruijing Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Bioinformatics and Biostatistics, SPHIS, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors.forename: Maiying
authors.initials: M
authors.lastname: Kong
authors.affiliation: Department of Neurosurgery, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brommer
authors.affiliation: Department of Laboratory Animal Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China. Electronic address: chenxuejin@shsmu.edu.cn.
authors.forename: Xuejin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Laboratory Animal Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China; Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: xu26@iupui.edu.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Xu
authors.affiliation: Norton Neuroscience Institute, Norton Healthcare, Louisville, KY 40202, USA; Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40292, USA. Electronic address: cbshields1@gmail.com.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Shields
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology; D001284:Atrophy; D001369:Axons / Q000473:pathology; D001522:Behavior, Animal; D003288:Contusions / Q000473:pathology* / Q000523:psychology; D004195:Disease Models, Animal; D019054:Evoked Potentials, Motor; D005073:Evoked Potentials, Somatosensory; D005911:Gliosis / Q000473:pathology; D006614:Hindlimb; D008124:Locomotion; D008253:Macaca mulatta; D008297:Male; D009186:Myelin Sheath / Q000473:pathology; D013116:Spinal Cord / Q000473:pathology; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000523:psychology
keywords: Behavior assessments; Contusion; Electrophysiology; Monkey; Non-human primate; Spinal cord injury