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Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here we introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, we delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury. Spatially selective and temporally controlled stimulation of the spinal cord, together with rehabilitation, results in substantial restoration of locomotor function in humans with spinal cord injury.

Remyelination via the transplantation of oligodendrocyte precursor cells (OPCs) has been considered as a strategy to improve the locomotor deficits caused by traumatic spinal cord injury (SCI). To date, enormous efforts have been made to derive OPCs from human pluripotent stem cells (hPSCs), and significant progress in the transplantation of such cells in SCI animal models has been reported. The current methods generally require a long period of time (>2 months) to obtain transplantable OPCs, which hampers their clinical utility for patients with SCI. Here we demonstrate a rapid and efficient method to differentiate hPSCs into neural progenitors that retain the features of OPCs (referred to as OPC-like cells). We used cell sorting to select A2B5-positive cells from hPSC-derived neural rosettes and cultured the selected cells in the presence of signaling cues, including sonic hedgehog, PDGF and insulin-like growth factor-1. This method robustly generated neural cells positive for platelet-derived growth factor receptor-α (PDGFRα) and NG2 (~90%) after 4 weeks of differentiation. Behavioral tests revealed that the transplantation of the OPC-like cells into the spinal cords of rats with contusive SCI at the thoracic level significantly improved hindlimb locomotor function. Electrophysiological assessment revealed enhanced neural conduction through the injury site. Histological examination showed increased numbers of axon with myelination at the injury site and graft-derived myelin formation with no evidence of tumor formation. Our method provides a cell source from hPSCs that has the potential to recover motor function following SCI. Spinal injury: Stimulating stem cells for repair A quick route to make cells that may repair spinal cord injuries moves researchers closer to the goal of treatments for paralysis in humans. Oligodendrocyte precursor cells (OPCs) generate the oligodendrocyte cells that build the insulating myelin sheaths around nerve fibers. They are believed to have potential for repairing damaged spinal cords, but difficulties producing them have hampered their application in clinical tests. Researchers in South Korea led by Joong Woo Leem and Dong-Wook Kim at Yonsei University have developed a rapid and efficient method to make OPC-like cells from human stem cells. The method selectively identifies and isolates suitable stem cells that can then be converted to OPC-like cells by treatment with signaling proteins and growth factors. Animal trials have shown the transplanted cells can partially repair spinal cord injuries without harmful side effects.

Purpose of ReviewSpinal cord injury (SCI) shows an incidence of 10.4–83 cases/million/year globally and remains a significant source of morbidity and cost to society. Despite greater understanding of the pathophysiology of SCI, neuroprotective and regenerative approaches to treatment have had limited clinical utility to date. Here, we review the key components of supportive care that are thus the mainstay of therapy and that have improved outcomes for victims of acute SCI in recent decades.Recent StudiesCurrent management strategies for acute SCI involve early surgical decompression and fixation, the use of vasopressor medications for mean arterial blood pressure (MAP) augmentation to improve spinal cord perfusion, and corticosteroids. We highlight recent literature supporting the role of norepinephrine in acute SCI management and also an emerging neurocritical care strategy that seeks to optimize spinal cord perfusion pressure with the assistance of invasive monitoring.SummaryThis review will highlight key pathophysiologic principles and targets for current acute clinical treatments in SCI, which include early surgical decompression, MAP augmentation, and corticosteroids. We discuss anticipated future research in these areas and focus on potential risks inherent to these treatments.

Mesenchymal stem cells (MSC) derived from bone marrow can potentially reduce the acute inflammatory response in spinal cord injury (SCI) and thus promote functional recovery. However, the precise mechanisms through which transplanted MSC attenuate inflammation after SCI are still unclear. The present study was designed to investigate the effects of MSC transplantation with a special focus on their effect on macrophage activation after SCI. Rats were subjected to T9–T10 SCI by contusion, then treated 3 days later with transplantation of 1.0×106 PKH26-labeled MSC into the contusion epicenter. The transplanted MSC migrated within the injured spinal cord without differentiating into glial or neuronal elements. MSC transplantation was associated with marked changes in the SCI environment, with significant increases in IL-4 and IL-13 levels, and reductions in TNF-α and IL-6 levels. This was associated simultaneously with increased numbers of alternatively activated macrophages (M2 phenotype: arginase-1- or CD206-positive), and decreased numbers of classically activated macrophages (M1 phenotype: iNOS- or CD16/32-positive). These changes were associated with functional locomotion recovery in the MSC-transplanted group, which correlated with preserved axons, less scar tissue formation, and increased myelin sparing. Our results suggested that acute transplantation of MSC after SCI modified the inflammatory environment by shifting the macrophage phenotype from M1 to M2, and that this may reduce the effects of the inhibitory scar tissue in the subacute/chronic phase after injury to provide a permissive environment for axonal extension and functional recovery.

Abstract BACKGROUND Human central nervous system stem cells (HuCNS-SC) are multipotent adult stem cells with successful engraftment, migration, and region-appropriate differentiation after spinal cord injury (SCI). OBJECTIVE To present data on the surgical safety profile and feasibility of multiple intramedullary perilesional injections of HuCNS-SC after SCI. METHODS Intramedullary free-hand (manual) transplantation of HuCNS-SC cells was performed in subjects with thoracic (n = 12) and cervical (n = 17) complete and sensory incomplete chronic traumatic SCI. RESULTS Intramedullary stem cell transplantation needle times in the thoracic cohort (20 M HuCNS-SC) were 19:30 min and total injection time was 42:15 min. The cervical cohort I (n = 6), demonstrated that escalating doses of HuCNS-SC up to 40 M range were well tolerated. In cohort II (40 M, n = 11), the intramedullary stem cell transplantation needle times and total injection time was 26:05 ± 1:08 and 58:14 ± 4:06 min, respectively. In the first year after injection, there were 4 serious adverse events in 4 of the 12 thoracic subjects and 15 serious adverse events in 9 of the 17 cervical patients. No safety concerns were considered related to the cells or the manual intramedullary injection. Cervical magnetic resonance images demonstrated mild increased T2 signal change in 8 of 17 transplanted subjects without motor decrements or emerging neuropathic pain. All T2 signal change resolved by 6 to 12 mo post-transplant. CONCLUSION A total cell dose of 20 M cells via 4 and up to 40 M cells via 8 perilesional intramedullary injections after thoracic and cervical SCI respectively proved safe and feasible using a manual injection technique.

Abstract BACKGROUND: Evidence indicates that, over time, patients with spinal cord injury (SCI) improve neurologically in various degrees. We sought to further investigate indicators of grade conversion in cervical SCI. OBJECTIVE: To detect predictors of ASIA impairment scale (AIS) grade conversion in SCI following surgical decompression. METHODS: In a retrospective study, demographics, clinical, imaging, and surgical data from 100 consecutive patients were assessed for predictors of AIS grade conversion. RESULTS: American Spinal Injury Association motor score was 17.1. AIS grade was A in 52%, B in 29%, and C in 19% of patients. Surgical decompression took place on an average of 17.6 h following trauma (≤12 h in 51 and >12 h in 49). Complete decompression was verified by magnetic resonance imaging (MRI) in 73 patients. Intramedullary lesion length (IMLL) on postoperative MRI measured 72.8 mm, and hemorrhage at the injury epicenter was noted in 71 patients. Grade conversion took place in 26.9% of AIS grade A patients, 65.5% of AIS grade B, and 78.9% of AIS grade C. AIS grade conversion had statistical relationship with injury severity score, admission AIS grade, extent of decompression, presence of intramedullary hemorrhage, American Spinal Injury Association motor score, and IMLL. A stepwise multiple logistic regression analysis indicated IMLL was the sole and strongest indicator of AIS grade conversion (odds ratio 0.950, 95% CI 0.931-0.969). For 1- and 10-mm increases in IMLL, the model indicates 4% and 40% decreases, respectively, in the odds of AIS grade conversion. CONCLUSION: Compared with other surrogates, IMLL remained as the only predictor of AIS grade conversion.

Cervical spinal cord injury (SCI) is a devastating condition with very few treatment options. It remains unclear if early surgery correlated with conversion of American Spinal Injury Association Impairment Scale (AIS) grade A injuries to higher grades. To determine the optimal time to surgery after cervical SCI through retrospective analysis. We collected data from 48 patients with cervical SCI. Based on the time from Emergency Department (ED) presentation to surgical decompression, we grouped patients into ultra-early (decompression within 12 h of presentation), early (within 12-24 h), and late groups (>24 h). We compared the improvement in AIS grade from admission to discharge, controlling for confounding factors such as AIS grade on admission, injury severity, and age. The mean time from injury to ED for this group of patients was 17 min. Patients who received surgery within 12 h after presentation had a relative improvement in AIS grade from admission to discharge: the ultra-early group improved on average 1.3. AIS grades compared to 0.5 in the early group (P = .02). In addition, 88.8% of patients with an AIS grade A converted to a higher grade (AIS B or better) in the ultra-early group, compared to 38.4% in the early and late groups (P = .054). These data suggest that surgical decompression after SCI that takes place within 12 h may lead to a relative improved neurological recovery compared to surgery that takes place after 12 h.

Various types of induced pluripotent stem (iPS) cells have been established by different methods, and each type exhibits different biological properties. Before iPS cell-based clinical applications can be initiated, detailed evaluations of the cells, including their differentiation potentials and tumorigenic activities in different contexts, should be investigated to establish their safety and effectiveness for cell transplantation therapies. Here we show the directed neural differentiation of murine iPS cells and examine their therapeutic potential in a mouse spinal cord injury (SCI) model. \"Safe\" iPS-derived neurospheres, which had been pre-evaluated as nontumorigenic by their transplantation into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse brain, produced electrophysiologically functional neurons, astrocytes, and oligodendrocytes in vitro. Furthermore, when the safe iPS-derived neurospheres were transplanted into the spinal cord 9 d after contusive injury, they differentiated into all three neural lineages without forming teratomas or other tumors. They also participated in remyelination and induced the axonal regrowth of host 5HT⁺ serotonergic fibers, promoting locomotor function recovery. However, the transplantation of iPS-derived neurospheres pre-evaluated as \"unsafe\" showed robust teratoma formation and sudden locomotor functional loss after functional recovery in the SCI model. These findings suggest that pre-evaluated safe iPS clone-derived neural stem/progenitor cells may be a promising cell source for transplantation therapy for SCI.

Although there is a strong biological rationale for early decompression of the injured spinal cord, the influence of the timing of surgical decompression for acute spinal cord injury (SCI) remains debated, with substantial variability in clinical practice. We aimed to objectively evaluate the effect of timing of decompressive surgery for acute SCI on long-term neurological outcomes. We did a pooled analysis of individual patient data derived from four independent, prospective, multicentre data sources, including data from December, 1991, to March, 2017. Three of these studies had been published; of these, only one study previously specifically analysed the effect of the timing of surgical decompression. These four datasets were selected because they were among the highest quality acute SCI datasets available and contained highly granular data. Individual patient data were obtained by request from study authors. All patients who underwent decompressive surgery for acute SCI within these datasets were included. Patients were stratified into early (<24 h after spinal injury) and late (≥24 h after spinal injury) decompression groups. Neurological outcomes were assessed by American Spinal Injury Association (ASIA), or International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), examination. The primary endpoint was change in total motor score from baseline to 1 year after spinal injury. Secondary endpoints were ASIA Impairment Scale (AIS) grade and change in upper-extremity motor, lower-extremity motor, light touch, and pin prick scores after 1 year. One-stage meta-analyses were done by hierarchical mixed-effects regression adjusting for baseline score, age, mechanism of injury, AIS grade, level of injury, and administration of methylprednisolone. Effect sizes were summarised by mean difference (MD) for sensorimotor scores and common odds ratio (cOR) for AIS grade, with corresponding 95% CIs. As a secondary analysis, change in total motor score was regressed against time to surgical decompression (h) as a continuous variable, using a restricted cubic spline with adjustment for the same covariates as in the primary analysis. We identified 1548 eligible patients from the four datasets. Outcome data at 1 year after spinal injury were available for 1031 patients (66·6%). Patients who underwent early surgical decompression (n=528) experienced greater recovery than patients who had late decompression surgery (n=1020) at 1 year after spinal injury; total motor scores improved by 23·7 points (95% CI 19·2–28·2) in the early surgery group versus 19·7 points (15·3–24·0) in the late surgery group (MD 4·0 points [1·7–6·3]; p=0·0006), light touch scores improved by 19·0 points (15·1–23·0) vs 14·8 points (11·2–18·4; MD 4·3 [1·6–7·0]; p=0·0021), and pin prick scores improved by 18·3 points (13·7–22·9) versus 14·2 points (9·8–18·6; MD 4·0 [1·5–6·6]; p=0·0020). Patients who had early decompression also had better AIS grades at 1 year after surgery, indicating less severe impairment, compared with patients who had late surgery (cOR 1·48 [95% CI 1·16–1·89]; p=0·0019). When time to surgical decompression was modelled as a continuous variable, there was a steep decline in change in total motor score with increasing time during the first 24–36 h after injury (p<0·0001); and after 36 h, change in total motor score plateaued. Surgical decompression within 24 h of acute SCI is associated with improved sensorimotor recovery. The first 24–36 h after injury appears to represent a crucial time window to achieve optimal neurological recovery with decompressive surgery following acute SCI. None.

There is convincing preclinical evidence that early decompression in the setting of spinal cord injury (SCI) improves neurologic outcomes. However, the effect of early surgical decompression in patients with acute SCI remains uncertain. Our objective was to evaluate the relative effectiveness of early (<24 hours after injury) versus late (≥ 24 hours after injury) decompressive surgery after traumatic cervical SCI. We performed a multicenter, international, prospective cohort study (Surgical Timing In Acute Spinal Cord Injury Study: STASCIS) in adults aged 16-80 with cervical SCI. Enrolment occurred between 2002 and 2009 at 6 North American centers. The primary outcome was ordinal change in ASIA Impairment Scale (AIS) grade at 6 months follow-up. Secondary outcomes included assessments of complications rates and mortality. A total of 313 patients with acute cervical SCI were enrolled. Of these, 182 underwent early surgery, at a mean of 14.2(± 5.4) hours, with the remaining 131 having late surgery, at a mean of 48.3(± 29.3) hours. Of the 222 patients with follow-up available at 6 months post injury, 19.8% of patients undergoing early surgery showed a ≥ 2 grade improvement in AIS compared to 8.8% in the late decompression group (OR = 2.57, 95% CI:1.11,5.97). In the multivariate analysis, adjusted for preoperative neurological status and steroid administration, the odds of at least a 2 grade AIS improvement were 2.8 times higher amongst those who underwent early surgery as compared to those who underwent late surgery (OR = 2.83, 95% CI:1.10,7.28). During the 30 day post injury period, there was 1 mortality in both of the surgical groups. Complications occurred in 24.2% of early surgery patients and 30.5% of late surgery patients (p = 0.21). Decompression prior to 24 hours after SCI can be performed safely and is associated with improved neurologic outcome, defined as at least a 2 grade AIS improvement at 6 months follow-up.