Rodent, large animal and non-human primate models of spinal cord injury

Zoology ◽  
2017 ◽  
Vol 123 ◽  
pp. 101-114 ◽  
Author(s):  
Raffaele Nardone ◽  
Cristina Florea ◽  
Yvonne Höller ◽  
Francesco Brigo ◽  
Viviana Versace ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Large Animal ◽  
Cord Injury ◽  
Human Primate

The Hemisection Approach in Large Animal Models of Spinal Cord Injury: Overview of Methods and Applications

2018 ◽  
Vol 33 (3) ◽  
pp. 240-251
Author(s):  
S. Wilson ◽  
S. J. Nagel ◽  
L. A. Frizon ◽  
D. C. Fredericks ◽  
N. A. DeVries-Watson ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Animal Models ◽  
Large Animal ◽  
Large Animal Models ◽  
Cord Injury

scholarly journals White matter regeneration induced by aligned fibrin nanofiber hydrogel contributes to motor functional recovery in canine T12 spinal cord injury

2021 ◽  
Author(s):  
Zheng Cao ◽  
Weitao Man ◽  
Yuhui Xiong ◽  
Yi Guo ◽  
Shuhui Yang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
White Matter ◽  
Nerve Regeneration ◽  
Spinal Cord Injuries ◽  
Diffusion Tensor ◽  
Nerve Fibers ◽  
Functional Restoration ◽  
Large Animal ◽  
Cord Injury

Abstract A hierarchically aligned fibrin hydrogel (AFG) that possesses soft stiffness and aligned nanofiber structure has been successfully proven to facilitate neuroregeneration in vitro and in vivo. However, its potential in promoting nerve regeneration in large animal models that is critical for clinical translation has not been sufficiently specified. Here, the effects of AFG on directing neuroregeneration in canine hemisected T12 spinal cord injuries were explored. Histologically obvious white matter regeneration consisting of a large area of consecutive, compact, and aligned nerve fibers is induced by AFG, leading to a significant motor functional restoration. The canines with AFG implantation start to stand well with their defective legs from 3 to 4 weeks postoperatively and even effortlessly climb the steps from 7 to 8 weeks. Moreover, high-resolution multi-shot diffusion tensor imaging illustrates the spatiotemporal dynamics of nerve regeneration rapidly crossing the lesion within 4 weeks in the AFG group. Our findings indicate that AFG could be a potential therapeutic vehicle for spinal cord injury by inducing rapid white matter regeneration and restoring locomotion, pointing out its promising prospect in clinic practice.

scholarly journals Nogo receptor decoy promotes recovery and corticospinal growth in non-human primate spinal cord injury

Brain ◽  
2020 ◽  
Vol 143 (6) ◽  
pp. 1697-1713 ◽  
Author(s):  
Xingxing Wang ◽  
Tianna Zhou ◽  
George D Maynard ◽  
Pramod S Terse ◽  
William B Cafferty ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Recovery Of Function ◽  
Neurological Deficits ◽  
Vehicle Group ◽  
Post Injury ◽  
Nogo Receptor ◽  
Human Dose ◽  
Cord Injury ◽  
Human Primate

Abstract After CNS trauma such as spinal cord injury, the ability of surviving neural elements to sprout axons, reorganize neural networks and support recovery of function is severely restricted, contributing to chronic neurological deficits. Among limitations on neural recovery are myelin-associated inhibitors functioning as ligands for neuronal Nogo receptor 1 (NgR1). A soluble decoy (NgR1-Fc, AXER-204) blocks these ligands and provides a means to promote recovery of function in multiple preclinical rodent models of spinal cord injury. However, the safety and efficacy of this reagent in non-human primate spinal cord injury and its toxicological profile have not been described. Here, we provide evidence that chronic intrathecal and intravenous administration of NgR1-Fc to cynomolgus monkey and to rat are without evident toxicity at doses of 20 mg and greater every other day (≥2.0 mg/kg/day), and far greater than the projected human dose. Adult female African green monkeys underwent right C5/6 lateral hemisection with evidence of persistent disuse of the right forelimb during feeding and right hindlimb during locomotion. At 1 month post-injury, the animals were randomized to treatment with vehicle (n = 6) or 0.10–0.17 mg/kg/day of NgR1-Fc (n = 8) delivered via intrathecal lumbar catheter and osmotic minipump for 4 months. One animal was removed from the study because of surgical complications of the catheter, but no treatment-related adverse events were noted in either group. Animal behaviour was evaluated at 6–7 months post-injury, i.e. 1–2 months after treatment cessation. The use of the impaired forelimb during spontaneous feeding and the impaired hindlimb during locomotion were both significantly greater in the treatment group. Tissue collected at 7–12 months post-injury showed no significant differences in lesion size, fibrotic scar, gliosis or neuroinflammation between groups. Serotoninergic raphespinal fibres below the lesion showed no deficit, with equal density on the lesioned and intact side below the level of the injury in both groups. Corticospinal axons traced from biotin-dextran-amine injections in the left motor cortex were equally labelled across groups and reduced caudal to the injury. The NgR1-Fc group tissue exhibited a significant 2–3-fold increased corticospinal axon density in the cervical cord below the level of the injury relative to the vehicle group. The data show that NgR1-Fc does not have preclinical toxicological issues in healthy animals or safety concerns in spinal cord injury animals. Thus, it presents as a potential therapeutic for spinal cord injury with evidence for behavioural improvement and growth of injured pathways in non-human primate spinal cord injury.

scholarly journals Epidural Stimulation Combined with Triple Gene Therapy for Spinal Cord Injury Treatment

2020 ◽  
Vol 21 (23) ◽  
pp. 8896
Author(s):  
Rustem Islamov ◽  
Farid Bashirov ◽  
Filip Fadeev ◽  
Roman Shevchenko ◽  
Andrei Izmailov ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Gene Therapy ◽  
Spinal Cord Injury ◽  
Combined Treatment ◽  
Small Sample ◽  
Functional Restoration ◽  
Synaptic Proteins ◽  
Large Animal ◽  
Cord Injury ◽  
Spinal Contusion

The translation of new therapies for spinal cord injury to clinical trials can be facilitated with large animal models close in morpho-physiological scale to humans. Here, we report functional restoration and morphological reorganization after spinal contusion in pigs, following a combined treatment of locomotor training facilitated with epidural electrical stimulation (EES) and cell-mediated triple gene therapy with umbilical cord blood mononuclear cells overexpressing recombinant vascular endothelial growth factor, glial-derived neurotrophic factor, and neural cell adhesion molecule. Preliminary results obtained on a small sample of pigs 2 months after spinal contusion revealed the difference in post-traumatic spinal cord outcomes in control and treated animals. In treated pigs, motor performance was enabled by EES and the corresponding morpho-functional changes in hind limb skeletal muscles were accompanied by the reorganization of the glial cell, the reaction of stress cell, and synaptic proteins. Our data demonstrate effects of combined EES-facilitated motor training and cell-mediated triple gene therapy after spinal contusion in large animals, informing a background for further animal studies and clinical translation.

scholarly journals Pediatric Spinal Cord Injury in Infant Piglets: Description of a New Large Animal Model and Review of the Literature

2010 ◽  
Vol 33 (1) ◽  
pp. 43-57 ◽  
Author(s):  
John Kuluz ◽  
Amer Samdani ◽  
David Benglis ◽  
Manuel Gonzalez-Brito ◽  
Juan P. Solano ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Animal Model ◽  
Large Animal Model ◽  
Large Animal ◽  
Review Of The Literature ◽  
Cord Injury ◽  
Pediatric Spinal Cord Injury

scholarly journals Humane Non-Human Primate Model of Traumatic Spinal Cord Injury: Quantitative Analysis of Electromyographic Data

2015 ◽  
Vol 05 (07) ◽  
pp. 161-168
Author(s):  
Nitin Seth ◽  
Farah Masood ◽  
John B. Sledge ◽  
William A. Graham ◽  
Douglas L. Rosene ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Quantitative Analysis ◽  
Traumatic Spinal Cord Injury ◽  
Primate Model ◽  
Cord Injury ◽  
Human Primate

scholarly journals Proteomic portraits reveal evolutionarily conserved and divergent responses to spinal cord injury

2021 ◽  
Author(s):  
Michael A. Skinnider ◽  
Jason Rogalski ◽  
Seth Tigchelaar ◽  
Neda Manouchehri ◽  
Anna Prudova ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Large Scale ◽  
Injury Severity ◽  
Large Animal ◽  
Serum Samples ◽  
Neurological Improvement ◽  
Cord Injury ◽  
Evolutionarily Conserved ◽  
Proteomic Analyses

Despite the emergence of promising therapeutic approaches in preclinical studies, the failure of large-scale clinical trials leaves clinicians without effective treatments for acute spinal cord injury (SCI). These trials are hindered by their reliance on detailed neurological examinations to establish outcomes, which inflate the time and resources required for completion. Moreover, therapeutic development takes place in animal models whose relevance to human injury remains unclear. Here, we address these challenges through targeted proteomic analyses of CSF and serum samples from 111 acute SCI patients and, in parallel, a large animal (porcine) model of SCI. We develop protein biomarkers of injury severity and recovery, including a prognostic model of neurological improvement at six months with an AUC of 0.91, and validate these in an independent cohort. Through cross-species proteomic analyses, we dissect evolutionarily conserved and divergent aspects of the SCI response, and establish the CSF abundance of glial fibrillary acidic protein (GFAP) as a biochemical outcome measure in both humans and pigs. Our work opens up new avenues to catalyze translation by facilitating the evaluation of novel SCI therapies, while also providing a resource from which to direct future preclinical efforts.

scholarly journals Serum MicroRNAs Reflect Injury Severity in a Large Animal Model of Thoracic Spinal Cord Injury

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Seth Tigchelaar ◽  
Femke Streijger ◽  
Sunita Sinha ◽  
Stephane Flibotte ◽  
Neda Manouchehri ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Animal Model ◽  
Injury Severity ◽  
Large Animal Model ◽  
Large Animal ◽  
Thoracic Spinal Cord ◽  
Thoracic Spinal ◽  
Cord Injury ◽  
Serum Micrornas
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