Traumatic Spinal Cord Injury Research Articles

Management of spinal trauma in pregnant patients: A systematic review of the literature.

Despite the high incidence of spine trauma globally, traumatic spinal cord injury (tSCI) during pregnancy is considered a rare medical emergency. The literature on acute management of these patients is sparse compared with that of mothers with preexisting tSCI. This systematic review aims to evaluate management strategies for tSCI during pregnancy in improving neurologic, obstetric, and neonatal outcomes. A systematic review of PubMed/MEDLINE was performed without language restriction from inception until November 2, 2023 for patients who acquired tSCI during pregnancy. Excluded articles described postpartum trauma, trauma before pregnancy, or SCI of nontraumatic etiology such as neoplastic, vascular, hemorrhagic, or ischemic origin. Primary outcomes investigated were maternal American Spinal Injury Association (ASIA) grade, pregnancy termination, cesarean delivery, prematurity, and neonatal adverse events. Data from 73 patients were extracted from 43 articles from 1955 to 2023. The mothers' median age was 24 years (interquartile range, 23-30 years), and the average gestational age at the time of injury was 21.1 ± 7.7 weeks. The thoracic spine was the most common segment affected (41.1%) and had the greatest proportion of complete tSCI (46.6%). Furthermore, ASIA score improvement was observed in 17 patients with 3 patients experiencing a 2-score improvement and 1 patient experiencing a 3-score improvement. Among these patients, 86% of ASIA B and 100% of ASIA C patients showed neurologic improvement, compared to only 17% of ASIA A patients. Surgically managed patients had a lower rate of neonatal adverse events than conservatively managed patients (11% vs. 34%). Acute tSCI requires a coordinated effort between a multidisciplinary team with careful consideration. While maternal neurologic improvement was observed more often following a better ASIA grade on presentation, the presence of neonatal adverse events was less common in patients treated with surgery than in patients who were managed conservatively. Systematic Review; Level IV.

An oil-in-gel type of organohydrogel loaded with methylprednisolone for the treatment of secondary injuries following spinal cord traumas

The secondary injuries following traumatic spinal cord injury (SCI) is a multiphasic and complex process that is difficult to treat. Although methylprednisolone (MP) is the only available pharmacological regime for SCI treatment, its efficacy remains controversial due to its very narrow therapeutic time window and safety concerns associated with high dosage. In this study, we have developed an oil-in-gel type of organohydrogel (OHG) in which the binary oleic-water phases coexist, for the local delivery of MP. This new OHG is fabricated by a glycol chitosan/oxidized hyaluronic acid hydrophilic network that is uniformly embedded with a biocompatible oil phase, and it can be effectively loaded with MP or other hydrophobic compounds. In addition to spatiotemporally control MP release, this biodegradable OHG also provides a brain tissue-mimicking scaffold that can promote tissue regeneration. OHG remarkably decreases the therapeutic dose of MP in animals and extends its treatment course over 21 d, thereby timely manipulating microglia/macrophages and their associated with signaling molecules to restore immune homeostasis, leading to a long-term functional improvement in a complete transection SCI rat model. Thus, this OHG represents a new type of gel for clinical treatment of secondary injuries in SCI.

A deep learning approach for cervical cord injury severity determination through axial and sagittal magnetic resonance imaging segmentation and classification.

Cross-sectional Database Study. While the American Spinal Injury Association (ASIA) Impairment Scale is the standard for assessing spinal cord injuries (SCI), it has limitations due to subjectivity and impracticality. Advances in machine learning (ML) and image recognition have spurred research into their use for outcome prediction. This study aims to analyze deep learning techniques for identifying and classifying cervical SCI severity from MRI scans. The study included patients with traumatic and nontraumatic cervical SCI admitted from 2019 to 2022. MRI images were labeled by two senior resident physicians. A deep convolutional neural network was trained using axial and sagittal cervical MRI images from the dataset. Model performance was assessed using Dice Score and IoU to measure segmentation accuracy by comparing predicted and ground truth masks. Classification accuracy was evaluated with the F1 Score, balancing false positives and negatives. In the axial spinal cord segmentation, we achieved a Dice score of 0.94 for and IoU score of 0.89. In the sagittal spinal cord segmentation, we obtained Dice score up to 0.9201 and IoU scores up to 0.8541. The model for axial image score classification gave a satisfactory result with an F1 score of 0.72 and AUC of 0.79. Our models successfully identified cervical SCI on T2-weighted MR images with satisfactory performance. Further research is needed to develop more advanced models for predicting patient outcomes in SCI cases.

Extracorporeal Shock Wave Therapy (eSWT) in Spinal Cord Injury-A Narrative Review.

Injury of the spinal cord causes motor and sensory dysfunction as well as pathological reflexes, leading to paraplegia or tetraplegia. The sequelae of traumatic spinal cord injury (SCI) are a significant burden and impact on healthcare systems. Despite constant progress in medicine, traumatic SCI still remains irreversible. To date, no satisfying treatment that can enable neuronal regeneration and recovery of function at the damaged level has been found. Hundreds of experiments have been conducted on various possibilities of influencing spinal regeneration; some of them have yielded promising results, but unfortunately, the successes obtained in experimental animals have not translated into humans. This narrative review article presents the application of extracorporeal shock wave therapy (eSWT) in patients with SCI. The article has been divided into parts: 1) use of extracorporeal shock wave therapy for regeneration of the spinal cord after traumatic spinal cord injury; 2) application of extracorporeal shock wave therapy in spasticity after spinal cord injury. In both cases, the hypotheses of possible mechanisms of action will be described. A small number of clinical trials have demonstrated the potential of eSWT to influence the regeneration of the spine, as an innovative, safe, and cost-effective treatment option for patients with SCI. Some reports have shown that eSWT can improve spasticity, walking ability, urological function, quality of life, and independence in daily life.

Omega-3 polyunsaturated fatty acids alleviate endoplasmic reticulum stress-induced neuroinflammation by protecting against traumatic spinal cord injury through the histone deacetylase 3/ peroxisome proliferator-activated receptor-γ coactivator pathway.

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) attenuate inflammatory responses in the central nervous system, leading to neuroprotective effects. Inhibition of histone deacetylase 3 (HDAC3) has neuroprotective effects after spinal cord injury (SCI) through the SIRT1 pathway, but the pathophysiological mechanisms of SCI are complex and the interactions between ω-3 PUFAs and organelles remain largely unknown. This study aimed to investigate the effect of ω-3 PUFAs on endoplasmic reticulum (ER) stress-induced neuroinflammation through the HDAC3/peroxisome proliferator-activated receptor-γ coactivator (PGC)-1ɑ pathway after SCI. To this end, a contusion-induced SCI rat model was established to evaluate the effects of ω-3 PUFAs on ER stress-mediated inflammation in SCI. ER stress was rapidly induced in spinal cord lesions after SCI and was significantly reduced after ω-3 PUFA treatment. Consistent with reduced ER stress, HDAC3 expression levels and inflammatory responses were decreased, and PGC-1ɑ expression levels were increased after SCI. We found that ω-3 PUFA treatment attenuated ER stress through HDAC3 inhibition, thereby reducing SCI-induced inflammation. Taken together, these results suggest a role for ω-3 PUFA in protecting against SCI-induced neuroinflammation and promoting neurological functional recovery by regulating the histone deacetylase 3/ peroxisome proliferator-activated receptor-γ coactivatorpathway.

Use of Long Spinal Board Post-Application of Protocol for Spinal Motion Restriction for Spinal Cord Injury.

Historically, prehospital care of trauma patients has included nearly universal use of a cervical collar (C-collar) and long spine board (LSB). Due to recent evidence demonstrating harm in using LSBs, implementation of new spinal motion restriction (SMR) protocols in the prehospital setting should reduce LSB use, even among patients with spinal cord injury. Our goal in this study was to evaluate the rates of and reasons for LSB use in high-risk patients-those with hospital-diagnosed spinal cord injury (SCI)-after statewide implementation of SMR protocols. Applying data from a state emergency medical services (EMS) registry to a state hospital discharge database, we identified cases in which a participating EMS agency provided care for a patient later diagnosed in the hospital with a SCI. Cases were then retrospectively reviewed to determine the prevalence of both LSB and C-collar use before and after agency adoption of a SMR protocol. We reviewed cases with LSB use after SMR protocol implementation to determine the motivations driving continued LSB use. We used simple descriptive statistics, odds ratios (OR) with 95% confidence intervals (CI) to describe the results. We identified 52 EMS agencies in the state of Arizona with 417,979 encounters. There were 225 patients with SCI, of whom 74 were excluded. The LSBs were used in 52 pre-SMR (81%) and 49 post-SMR (56%) cases. The odds of LSB use after SMR protocol implementation was 70% lower than it had been before implementation (OR 0.297, 95% CI 0.139-0.643; P = 0.002). Use of a C-collar after SMR implementation was not significantly changed (OR 0.51, 95% CI 0.23-1.143; P = 0.10). In the 49 cases of LSB use after agency SMR implementation, the most common reasons for LSB placement were ease of lifting (63%), placement by non-transporting agency (18%), and extrication (16.3%). High suspicion of SCI was determined as the primary or secondary reason for not removing LSB after assessment in 63% of those with LSB placement, followed by multiple transfers required (20%), and critical illness (10%). Implementation of selective spinal motion restriction protocols was associated with a statistically significant decrease in the utilization of long spine boards among prehospital patients with acute traumatic spinal cord injury.

Outcomes and implications of pediatric spinal gun shot wounds: A cross-sectional analysis using 2017-2021 TQIP data

BackgroundPediatric morbidity and mortality due to gun violence has steadily risen in recent years, becoming the leading cause of death among children and teens as of 2022 per the Center for Disease Control (CDC). For patients under the age of 17 in the United States, gunshot wounds (GSWs) are the underlying cause of traumatic spinal cord injury (tSCI) in 8.3% of patients. Although prior studies have examined the broader trends of firearm-related deaths in children, investigation specifically focusing on gunshot wounds to the spine has not addressed the pediatric population. MethodsThe TQIP database from 2017 to 2021 was queried for patients under the age of 18 with gunshot traumas, and ICD-10 diagnosis codes were used to identify associated spinal injuries. The incidence across time and risk factors for adverse hospital outcomes were analyzed using multivariate logistic regression. Factors of interest included demographic characteristics, insurance provider, and comorbidities. ResultsA total of 3,155 gunshot injuries to the spine (GSIS) in the pediatric population were reported to TQIP between 2017 and 2021. Average patient age was 16 ± 2.8 years old and the majority of patients (n=1819, 57.6%) were uninsured. Assault was the intent of firearm discharge in 2,582 (81.8%) patients and unintentional injury occurred in 322 (10.2%) cases. Mortality occurred in 11.7% of GSIS, twice that of the 5.8% seen in all pediatric GSW. Those with psychiatric disorders were more likely to result in extended LOS (OR, 2.538; 95% CI, 1.638-3.932; P < 0.001) and in-hospital complications (OR, 1.841; 95% CI, 1.139-2.891; P = 0.012) when analyzed with multivariate binomial logistic regression. ConclusionIn this large-scale retrospective study using TQIP data, we identified trends in spine injuries sustained from gun trauma in the pediatric population. Consideration of demographics, hospital course, and outcomes as examined in this study can provide valuable insights to clinicians, public health organizations, and policy makers.

A biomimic anti-neuroinflammatory nanoplatform for active neutrophil extracellular traps targeting and spinal cord injury therapy

Traumatic spinal cord injury (SCI) always leads to severe neurological deficits and permanent damage. Neuroinflammation is a vital process of SCI and have become a promising target for SCI treatment. However, the neuroinflammation-targeted therapy would hinder the functional recovery of spinal cord and lead to the treatment failure. Herein, a biomimic anti-neuroinflammatory nanoplatform (DHCNPs) was developed for active neutrophil extracellular traps (NETs) targeting and SCI treatment. The curcumin-loaded liposome with the anti-inflammatory property acted as the core of the DHCNPs. Platelet membrane and neutrophil membrane were fused to form the biomimic hybrid membrane of the DHCNPs for hijacking neutrophils and neutralizing the elevated neutrophil-related proinflammatory cytokines, respectively. DNAse I modification on the hybrid membrane could achieve NETs degradation, blood spinal cord barrier, and neuron repair. Further studies proved that the DHCNPs could reprogram the multifaceted neuroinflammation and reverse the SCI process via nuclear factor kappa-B (NF-κB) pathway. We believe that the current study provides a new perspective for neuroinflammation inhibition and may shed new light on the treatment of SCI.

Axonal Growth and Fasciculation of Spinal Neurons Promoted by Aldynoglia in Alkaline Fibrin Hydrogel: Influence of Tol-51 Sulfoglycolipid.

Traumatic spinal cord injury (tSCI) has complex pathophysiological events that begin after the initial trauma. One such event is fibroglial scar formation by fibroblasts and reactive astrocytes. A strong inhibition of axonal growth is caused by the activated astroglial cells as a component of fibroglial scarring through the production of inhibitory molecules, such as chondroitin sulfate proteoglycans or myelin-associated proteins. Here, we used neural precursor cells (aldynoglia) as promoters of axonal growth and a fibrin hydrogel gelled under alkaline conditions to support and guide neuronal cell growth, respectively. We added Tol-51 sulfoglycolipid as a synthetic inhibitor of astrocyte and microglia in order to test its effect on the axonal growth-promoting function of aldynoglia precursor cells. We obtained an increase in GFAP expression corresponding to the expected glial phenotype for aldynoglia cells cultured in alkaline fibrin. In co-cultures of dorsal root ganglia (DRG) and aldynoglia, the axonal growth promotion of DRG neurons by aldynoglia was not affected. We observed that the neural precursor cells first clustered together and then formed niches from which aldynoglia cells grew and connected to groups of adjacent cells. We conclude that the combination of alkaline fibrin with synthetic sulfoglycolipid Tol-51 increased cell adhesion, cell migration, fasciculation, and axonal growth capacity, promoted by aldynoglia cells. There was no negative effect on the behavior of aldynoglia cells after the addition of sulfoglycolipid Tol-51, suggesting that a combination of aldynoglia plus alkaline fibrin and Tol-51 compound could be useful as a therapeutic strategy for tSCI repair.

Prehospital guidelines on in-water traumatic spinal injuries for lifeguards and prehospital emergency medical services: an international Delphi consensus study

BackgroundTrauma guidelines on spinal motion restriction (SMR) have changed drastically in recent years. An international group of experts explored whether consensus could be reached and if guidelines on SMR performed by trained lifeguards and prehospital EMS following in-water traumatic spinal cord injury (TSCI) should also be changed.MethodsAn international three-round Delphi process was conducted from October 2022 to November 2023. In Delphi round one, brainstorming resulted in an exhaustive list of recommendations for handling patients with suspected in-water TSCI. The list was also used to construct a preliminary flowchart for in-water SMR. In Delphi round two, three levels of agreement for each recommendation and the flowchart were established. Recommendations with strong consensus (≥ 85% agreement) underwent minor revisions and entered round three; recommendations with moderate consensus (75–85% agreement) underwent major revisions in two consecutive phases; and recommendations with weak consensus (< 75% agreement) were excluded. In Delphi round 3, the level of consensus for each of the final recommendations and each of the routes in the flowchart was tested using the same procedure as in Delphi round 2.ResultsTwenty-four experts participated in Delphi round one. The response rates for Delphi rounds two and three were 92% and 88%, respectively. The study resulted in 25 recommendations and one flowchart with four flowchart paths; 24 recommendations received strong consensus (≥ 85%), and one recommendation received moderate consensus (81%). Each of the four paths in the flowchart received strong consensus (90–95%). The integral flowchart received strong consensus (93%).ConclusionsThis study produced expert consensus on 25 recommendations and a flowchart on handling patients with suspected in-water TSCI by trained lifeguards and prehospital EMS. These results provide clear and simple guidelines on SMR, which can standardise training and guidelines on SMR performed by trained lifeguards or prehospital EMS.

Regeneration and Plasticity Induced by Epidural Stimulation in a Rodent Model of Spinal Cord Injury.

Traumatic spinal cord injury is a major cause of disability for which there are currently no fully effective treatments. Recent studies using epidural electrical stimulation have shown significant advances in motor rehabilitation, even when applied during chronic phases of the disease. The present study aimed to investigate the effectiveness of epidural electric stimulation in the motor recovery of rats with spinal cord injury. Furthermore, we aimed to elucidate the neurophysiological mechanisms underlying motor recovery. First, we improved upon the impact spinal cord injury model to cause severe and permanent motor deficits lasting up to 2 months. Next, we developed and tested an implantable epidural spinal cord stimulator device for rats containing an electrode and an implantable generator. Finally, we evaluated the efficacy of epidural electrical stimulation on motor recovery after spinal cord injury in Wistar rats. A total of 60 animals were divided into the following groups: (i) severe injury with epidural electrical stimulation (injury + stim, n = 15), (ii) severe injury without stimulation (group injury, n = 15), (iii) sham implantation without battery (sham, n = 15), and (iv) a control group, without surgical intervention (control, n = 15). All animals underwent weekly evaluations using the Basso, Beattie, Bresnahan (BBB) locomotor rating scale index, inclined plane, and OpenField test starting one week before the lesion and continuing for eight weeks. After this period, the animals were sacrificed and their spinal cords were explanted and prepared for histological analysis (hematoxylin-eosin) and immunohistochemistry for NeuN, β-III-tubulin, synaptophysin, and Caspase 3. Finally, NeuN-positive neuronal nuclei were quantified through stereology; fluorescence signal intensities for β-tubulin, synaptophyin, and Caspase 3 were quantified using an epifluorescence microscope. The injury + stim group showed significant improvement on the BBB scale compared with the injured group after the 5th week (p < 0.05). Stereological analysis showed a significantly higher average count of neural cells in the injury + stim group in relation to the injury group (1783 ± 2 vs. 897 ± 3, p < 0.001). Additionally, fluorescence signal intensity for synaptophysin was significantly higher in the injury + stim group in relation to the injury group (1294 ± 46 vs. 1198 ± 23, p < 0.01); no statistically significant difference was found in β-III-tubulin signal intensity. Finally, Caspase 3 signal intensity was significantly lower in the stim group (727 ± 123) compared with the injury group (1225 ± 87 p < 0.05), approaching levels observed in the sham and control groups. Our data suggest a regenerative and protective effect of epidural electrical stimulation in rats subjected to impact-induced traumatic spinal cord injury.

The Current Update of Conventional and Innovative Treatment Strategies for Central Nervous System Injury.

This review explores the complex challenges and advancements in the treatment of traumatic brain injury (TBI) and spinal cord injury (SCI). Traumatic injuries to the central nervous system (CNS) trigger intricate pathophysiological responses, frequently leading to profound and enduring disabilities. This article delves into the dual phases of injury-primary impacts and the subsequent secondary biochemical cascades-that worsen initial damage. Conventional treatments have traditionally prioritized immediate stabilization, surgical interventions, and supportive medical care to manage both the primary and secondary damage associated with central nervous system injuries. We explore current surgical and medical management strategies, emphasizing the crucial role of rehabilitation and the promising potential of stem cell therapies and immune modulation. Advances in stem cell therapy, gene editing, and neuroprosthetics are revolutionizing treatment approaches, providing opportunities not just for recovery but also for the regeneration of impaired neural tissues. This review aims to emphasize emerging therapeutic strategies that hold promise for enhancing outcomes and improving the quality of life for affected individuals worldwide.

P320. Traumatic spinal cord injury over the last 30 years in North America - a decades-based analysis

P320. Traumatic spinal cord injury over the last 30 years in North America - a decades-based analysis

P319. Time to 50% recovery after traumatic spinal cord injury may be a more meaningful outcome measure than absolute total motor score recovery; a novel analysis of the SYGEN multicenter randomized control study

P319. Time to 50% recovery after traumatic spinal cord injury may be a more meaningful outcome measure than absolute total motor score recovery; a novel analysis of the SYGEN multicenter randomized control study

Neuromotor decline is associated with gut dysbiosis following surgical decompression for Degenerative Cervical Myelopathy

Degenerative cervical myelopathy (DCM) describes a spectrum of disorders that cause progressive and chronic cervical spinal cord compression. The clinical presentation can be complex and can include locomotor impairment, hand and upper extremity dysfunction, pain, loss of bladder and bowel function, as well as gastrointestinal dysfunction. Once diagnosed, surgical decompression is the recommended treatment for DCM patients with moderate to severe impairment.Our body is composed of a large community of microorganisms, known as the microbiota. Traumatic and non-traumatic spinal cord injuries (SCIs) can induce changes in the gut microbiota and gut microbiota derived metabolites. These changes have been reported as important disease-modifying factors after injury. However, whether gut dysbiosis is associated with functional neurological recovery after surgical decompression has not been examined to date.Here, DCM was induced in C57BL/6 mice by implanting an aromatic polyether material underneath the C5–6 laminae. The extent of gut dysbiosis was assessed by gas chromatography and 16S rRNA sequencing from fecal samples before and after decompression. Neuromotor activity was assessed using the Catwalk test.Our results show that DCM pre- and post- surgical decompression is associated with gut dysbiosis, without altering short chain fatty acids (SCFAs) levels. Significant differences in Clostridia, Verrumicrobiae, Lachnospiracea, Firmicutes, Bacteroidales, and Clostridiaceae were observed between the DCM group (before decompression) and after surgical decompression (2 and 5 weeks). The changes in gut microbiota composition correlated with locomotor features of the Catwalk. For example, a longer duration of ground contact and dysfunctional swing in the forelimbs, were positively correlated with gut dysbiosis. These results show for the first time an association between gut dysbiosis and locomotor deterioration after delayed surgical decompression. Thus, providing a better understanding of the extent of changes in microbiota composition in the setting of DCM pre- and post- surgical decompression.

P318. SYGEN (GM1 Ganglioside) promotes faster recovery after traumatic spinal cord injury compared to placebo; a contemporary analysis of the SYGEN multicenter randomized control study

P318. SYGEN (GM1 Ganglioside) promotes faster recovery after traumatic spinal cord injury compared to placebo; a contemporary analysis of the SYGEN multicenter randomized control study

Association of systemic inflammatory response index and clinical outcome in acute traumatic spinal cord injury patients

Systemic inflammatory response index (SIRI) has been proven to be associated with the prognosis of coronary artery disease and many other diseases. However, the relationship between SIRI and acute traumatic spinal cord injury (tSCI) has rarely been evaluated. The study aims to assess the prognostic value of SIRI for clinical outcomes in individuals with acute tSCI. A total of 190 patients admitted within eight hours after tSCI between January 2021 and April 2023 were enrolled in our study. Logistic regression analysis was used to analyze the association between SIRI and American Spinal Injury Association Impairment Scale (AIS) grade at admission and discharge, as well as neurological improvement in tSCI patients, and receiver operating characteristic (ROC) analysis was performed to assess the discriminative ability of SIRI in predicting AIS grade at discharge. After adjusting for confounding factors, SIRI positively correlated with the AIS grade (A to C) at admission and discharge, and negatively correlated with neurological improvement. The area under the curve values in ROC analysis was 0.725 (95% CI 0.647, 0.803). The study suggests that SIRI is significantly associated with an increased risk of poor clinical outcome at discharge in tSCI patients and has a certain discriminative value.

Paramedullary plasma cell myeloma originating from the first cervical vertebra (C1) in an 8‐month‐old Warmblood with tetraparesis: Clinical and pathological findings

SummaryTo the authors' knowledge there is only one report in the literature describing plasma cell paramedullary myeloma in horses as so‐called ‘break out lesions’, originating from vertebral bone marrow and invading the epidural space. This report describes clinical and pathomorphological findings of such. An 8‐month‐old Warmblood colt exhibited acute tetraparesis and a cervical column spinal cord lesion was suspected. Computed tomography revealed C1 osteolytic lesions by a heterogeneous mass. By pathomorphological examination including transmission electron microscopy, a plasma cell myeloma was identified, locally compressing the spinal cord. In tetraparetic young horses traumatic spinal cord injuries, cervical vertebral malformations, and central nervous system infectious diseases represent common differentials. However, osteolytic tumours such as paramedullary (plasma cell) myelomas, as space occupying lesion due to vertebral canal intrusion, should be considered as a cause for severe neurological deficits.

Corticothalamic input derived from corticospinal neurons contributes to chronic neuropathic pain after spinal cord injury

Neuropathic pain is a significant and persistent issue for individuals with spinal cord injuries (SCI), severely impacting their quality of life. While changes at the peripheral and spinal levels are known to contribute to SCI-related pain, whether and how supraspinal centers contribute to post SCI chronic neuropathic pain is poorly understood. Here, we first validated delayed development of chronic neuropathic pain in mice with moderate contusion SCI. To identify supraspinal regions involved in the pathology of neuropathic pain after SCI, we next performed an activity dependent genetic screening and identified multiple cortical and subcortical regions that were activated by innocuous tactile stimuli at a late stage following contusion SCI. Notably, chemogenetic inactivation of pain trapped neurons in the lateral thalamus alleviated neuropathic pain and reduced tactile stimuli evoked cortical overactivation. Retrograde tracing showed that contusion SCI led to enhanced corticothalamic axonal sprouting and over-activation of corticospinal neurons. Mechanistically, ablation or silencing of corticospinal neurons prevented the establishment or maintenance of chronic neuropathic pain following contusion SCI. These results highlighted a corticospinal-lateral thalamic feed-forward loop whose activation is required for the development and maintenance of chronic neuropathic pain after SCI. Our data thus shed lights into the central mechanisms underlying chronic neuropathic pain associated with SCI and the development of novel therapeutic avenues to treat refractory pain caused by traumatic brain or spinal cord injuries.

Safety and feasibility of intravenous administration of a single dose of allogenic-Muse cells to treat human cervical traumatic spinal cord injury: a clinical trial

IntroductionSpinal cord injury (SCI) is a devastating injury and remains one of the largest medical and social burdens because of its intractable nature. According to the recent advances in stem cell biology, the possibility of spinal cord regeneration and functional restoration has been suggested by introducing appropriate stem cells. Multilineage-differentiating stress enduring (Muse) cells are a type of nontumorigenic endogenous reparative stem cell. The positive results of Muse cell transplantation for SCI was shown previously. As a first step for clinical application in human SCI, we conducted a clinical trial aiming to confirm the safety and feasibility of intravenously injected donor-Muse cells.MethodsThe study design of the current trial was a prospective, multicenter, nonrandomized, nonblinded, single-arm study. The clinical trial registration number was JRCT1080224764. Patients with a cervical SCI with a neurological level of injury C4 to C7 with the severity of modified Frankel classification B1 and B2 were included. A primary endpoint was set for safety and feasibility. Our protocol was approved by the PMDA, and the trial was funded by the Life Science Institute, Tokyo, Japan. The present clinical trial recruited 10 participants (8 males and 2 females) with an average age of 49.3 ± 21.2 years old. All 10 participants received a single dose of allogenic CL2020 (a total of 15 × 106 cells, 2.1–2.7 × 105 cells/kg of body weight), which is a Muse cell-based product produced from human mesenchymal stem cells, by an intravenous drip.ResultsThere were two reported severe adverse events, both of which were determined to have no causal relationship with Muse cell treatment. The change in the ISNCSCI motor score, the activity of daily living and quality of life scores showed statistically significant improvements compared to those data at the time of CL2020 administration.ConclusionIn the present trial, no safety concerns were identified, and Muse cell product transplantation demonstrated good tolerability. Future clinical trials with appropriate study designs incorporating a control arm will clarify the definitive efficacy of single-dose allogenic Muse cell treatment with intravenous administration to treat SCI.Trial registration: jRCT, JRCT1080224764. Registered 03 July 2019, https://jrct.niph.go.jp/latest-detail/jRCT1080224764.