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Chronic spinal cord injury (SCI) is a devastating medical condition. In the acute phase after injury, there is cell loss resulting in chronic axonal damage and loss of sensory and motor function including loss of oligodendrocytes that results in demyelination of axons and further dysfunction. In the chronic phase, the inhibitory environment within the lesion including the glial scar can arrest axonal growth and regeneration and can also potentially affect transplanted cells. We hypothesized that glial scar ablation (GSA) along with cell transplantation may be required as a combinatorial therapy to achieve functional recovery, and therefore we proposed to examine the survival and fate of human induced pluripotent stem cell (iPSC) derived pre-oligodendrocyte progenitor cells (pre-OPCs) transplanted in a model of chronic SCI, whether this was affected by GSA, and whether this combination of treatments would result in functional recovery. In this study, chronically injured athymic nude (ATN) rats were allocated to one of three treatment groups: GSA only, pre-OPCs only, or GSA+pre-OPCs. We found that human iPSC derived pre-OPCs were multi-potent and retained the ability to differentiate into mainly oligodendrocytes or neurons when transplanted into the chronically injured spinal cords of rats. Twelve weeks after cell transplantation, we observed that more of the transplanted cells differentiated into oligodendrocytes when the glial scar was ablated compared with no GSA. Further, we also observed that a higher percentage of transplanted cells differentiated into V2a interneurons and motor neurons in the pre-OPCs only group when compared with GSA+pre-OPCs. This suggests that the local environment created by ablation of the glial scar may have a significant effect on the fate of cells transplanted into the injury site.

Epidural spinal cord stimulation (eSCS) has been recently recognized as a potential therapy for chronic spinal cord injury (SCI). eSCS has been shown to uncover residual pathways within the damaged spinal cord. The purpose of this review is to summarize the key findings to date regarding the use of eSCS in SCI. Searches were carried out using MEDLINE, EMBASE, and Web of Science database and reference lists of the included articles. A combination of medical subject heading terms and keywords was used to find studies investigating the use of eSCS in SCI patients to facilitate volitional movement and to restore autonomic function. The risk of bias was assessed using Risk Of Bias In Non-Randomized Studies of Interventions tool for nonrandomized studies. We were able to include 40 articles that met our eligibility criteria. The studies included a total of 184 patient experiences with incomplete or complete SCI. The majority of the studies used the Medtronic 16 paddle lead. Around half of the studies reported lead placement between T11- L1. We included studies that assessed motor (

Epidural Spinal Cord Stimulation (eSCS) in combination with extensive rehabilitation has been reported to restore volitional movement in a select group of subjects after motor-complete spinal cord injury (SCI). Numerous questions about the generalizability of these findings to patients with longer term SCI have arisen, especially regarding the possibility of restoring autonomic function. To better understand the effect of eSCS on volitional movement and autonomic function, two female participants five and 10 years after injury at ages 48 and 52, respectively, with minimal spinal cord preservation on magnetic resonance imaging were implanted with an eSCS system at the vertebral T12 level. We demonstrated that eSCS can restore volitional movement immediately in two female participants in their fifth and sixth decade of life with motor and sensory-complete SCI, five and 10 years after sustaining severe radiographic injuries, and without prescribed or significant pre-habilitation. Both patients experienced significant improvements in surface electromyography power during a volitional control task with eSCS on. Cardiovascular function was also restored with eSCS in one participant with cardiovascular dysautonomia using specific eSCS settings during tilt challenge while not affecting function in a participant with normal cardiovascular function. Orgasm was achieved for the first time since injury in one participant with and immediately after eSCS. Bowel-bladder synergy improved in both participants while restoring volitional urination in one with eSCS. While numerous questions remain, the ability to restore some supraspinal control over motor function below the level of injury, cardiovascular function, sexual function, and bowel and bladder function should promote intense efforts to investigate and develop optimization strategies to maximize recovery in all participants with chronic SCI.

There are no effective therapies available currently to ameliorate loss of function for patients with spinal cord injuries (SCIs). In addition, proposed treatments that demonstrated functional recovery in animal models of acute SCI have failed almost invariably when applied to chronic injury models. Glial scar formation in chronic injury is a likely contributor to limitation on regeneration. We have removed existing scar tissue in chronically contused rat spinal cord using a rose Bengal-based photo ablation approach. In this study, we compared two chemically modified rose bengal derivatives to unmodified rose bengal, both confirming and expanding on our previously published report. Rats were treated with unmodified rose bengal (RB1) or rose bengal modified with hydrocarbon (RB2) or polyethylene glycol (RB3), to determine the effects on scar components and spared tissue post-treatment. Our results showed that RB1 was more efficacious than RB2, while still maintaining minimal collateral effects on spared tissue. RB3 was not taken up by the cells, likely because of its size, and therefore had no effect. Treatment with RB1 also resulted in an increase in serotonin eight days post-treatment in chronically injured spinal cords. Thus, we suggest that unmodified rose Bengal is a potent candidate agent for the development of a therapeutic strategy for scar ablation in chronic SCI.

Stem/progenitor cells derived from the ependymal region of the spinal cord have the ability to self-renew and are multipotential for neurons and glia. These cells may have the ability to regenerate the injured mammalian spinal cord as they do in some lower vertebrates. However, the optimal conditions for transplantation and the fate of transplanted cells are not fully known. In the current study, spinal cord stem/progenitor cells were cultured from adult male rats expressing enhanced green fluorescent protein (eGFP). Neurospheres were transplanted at the time of clip compression injury (35-g force) into the injury site, or 1 mm rostral and caudal to the injury site. Neurospheres were also transplanted into a subacute model (day 9 after injury) and a chronic model (day 28 after injury). Functional recovery was also studied in an acute injury model with weekly locomotor testing over a 16-week period. A significant increase in cell survival at 7 days was seen in rats receiving rostral and caudal injections as compared to injection directly into the site of injury. A significant increase in cell survival was also seen in rats receiving subacute transplants at 9 days after injury. Transplanted cells differentiated primarily into astrocytes (31.2%) and oligodendrocytes (50.3%), and a small number of neurons (1%). No improvement was seen in the Basso, Beattie and Bresnahan (BBB) locomotor rating scale after acute transplantation as compared with injury only, although surviving transplanted cells were identified that had migrated across the injury site from the rostral and caudal injection sites.