A Cervical Hemi-Contusion Spinal Cord Injury Model for the Investigation of Novel Therapeutics Targeting Proximal and Distal Forelimb Functional Recovery

Abstract

Cervical spinal cord contusion is the most common human spinal cord injury, yet few rodent models replicate the pathophysiological and functional sequela of this injury. Here, we modified an electromechanical injury device and characterized the behavioral and histological changes occurring in response to a lateralized C4 contusion injury in rats. A key feature of the model includes a non-injurious touch phase where the spinal cord surface is dimpled with a consistent starting force. Animals were either left intact as a control, received a non-injury-producing touch on the surface of the cord (''sham''), or received a 0.6 mm or a 0.8 mm displacement injury. Rats were then tested on the forelimb asymmetry use test, CatWalk, and the Irvine, Beatties, and Bresnahan (IBB) cereal manipulation task to assess proximal and distal upper limb function for 12 weeks. Injuries of moderate (0.6 mm) and large (0.8 mm) displacement showed consistent differences in forelimb asymmetry, metrics of the CatWalk, and sub-scores of the IBB. Overall findings indicated long lasting proximal and distal upper limb deficits following 0.8 mm injury but transient proximal with prolonged distal limb deficits following 0.6 mm injury. Significant differences in loss of ipsilateral unmyelinated and myelinated white matter was detected between injury severities. Demyelination was primarily localized to the dorsolateral region of the hemicord and extended further rostral following 0.8 mm injury. These findings establish the C4 hemi-contusion injury as a consistent, graded model for testing novel treatments targeting forelimb functional recovery.

Fabrication of homotypic neural ribbons as a multiplex platform optimized for spinal cord delivery

“…Contusion injury is the most prevalent form of SCI in humans. Here using a relevant rat C4 hemi-contusion model 16 , we demonstrate that minimally invasive delivery of scNSC neural ribbons by syringe injection into the contused injury cavity reproducibly achieves cell survival and retention with as few as 5,000 cells. Traditional NSC methods in rat models typically deliver cells in a dose range of 200,000 to 2 million cells.…”

“…Lateral right-sided C4 hemi-contusion lesions were induced with moderate displacement (0.8 mm) in 4-month-old female Long-Evans rats (N = 6) as previously described 16 . Four animals received neural ribbons and two animals received scNSCs delivered in suspension.…”

“…Neural ribbons are durable, and can be prepared at one location and shipped off-site for animal studies. We apply a well-established rat C4 hemi-contusion injury model 16 to validate neural ribbon delivery by syringe injection. Homotypic cervical scNSCs from neural ribbon grafts survive and are retained in the injury cavity, projecting neurites into host tissue that co-localize with Synapsin.…”

Rapamycin Preserves Neural Tissue, Promotes Schwann Cell Myelination and Reduces Glial Scar Formation After Hemi-Contusion Spinal Cord Injury in Mice

“…White matter loss can be observed at the epicenter of the spinal cord after SCI (Rowland et al, 2008;Mondello et al, 2015;Zhang et al, 2016), as reflected by the loss of myelin sheaths. The aggregation of inflammatory cells, the release of inflammatory factors, and the phagocytosis of myelin debris by macrophages FIGURE 7 | Rapamycin alters the activation of astrocytes and glial scar formation at the epicenter of spinal cord after injury.…”

This preprint has been taken down.

“…Here we demonstrate a brain-computer-spinal interface (BCSI) that decodes movement intention from the motor cortex and subsequently stimulates the cervical spinal cord via epidural stimulation below the injury. This system resulted marked improvements in forelimb function after a clinically-realistic cervical contusion injury 24 .…”