From single to combinatorial therapies in spinal cord injuries for structural and functional restoration

Spinal cord injury results in paralysis, sensory disturbances, sphincter dysfunction, and multiple systemic secondary conditions, most arising from autonomic dysregulation. All this produces profound negative psychosocial implications for affected people, their families, and their communities;the financial costs can be challenging for their families and health institutions. Treatments aimed at restoring the spinal cord after spinal cord injury, which have been tested in animal models or clinical trials, generally seek to counteract one or more of the secondary mechanisms of injury to limit the extent of the initial damage. Most published works on structural/functional restoration in acute and chronic spinal cord injury stages use a single type of treatment: a drug or trophic factor, transplant of a cell type, and implantation of a biomaterial. Despite the significant benefits reported in animal models, when translating these successful therapeutic strategies to humans, the result in clinical trials has been considered of little relevance because the improvement, when present, is usually insufficient. Until now, most studies designed to promote neuroprotection or regeneration at different stages after spinal cord injury have used single treatments. Considering the occurrence of various secondary mechanisms of injury in the acute and sub-acute phases of spinal cord injury, it is reasonable to speculate that more than one therapeutic agent could be required to promote structural and functional restoration of the damaged spinal cord. Treatments that combine several therapeutic agents, targeting different mechanisms of injury, which, when used as a single therapy, have shown some benefits, allow us to assume that they will have synergistic beneficial effects. Thus, this narrative review article aims to summarize current trends in the use of strategies that combine therapeutic agents administered simultaneously or sequentially, seeking structural and functional restoration of the injured spinal cord.

Decision-Making and Management of Self-Care in Persons with Traumatic Spinal Cord Injuries: A Preliminary Study

Patients and physicians understand the importance of self-care following spinal cord injury (SCI), yet many individuals with SCI do not adhere to recommended self-care activities despite logistical supports. Neurobehavioral determinants of SCI self-care behavior, such as impulsivity, are not widely studied, yet understanding them could inform efforts to improve SCI self-care. We explored associations between impulsivity and self-care in an observational study of 35 US adults age 18 - 50 who had traumatic SCI with paraplegia at least six months before assessment. The primary outcome measure was self-reported self-care. In LASSO regression models that included all neurobehavioral measures and demographics as predictors of self-care, dispositional measures of greater impulsivity (negative urgency, lack of premeditation, lack of perseverance), and reduced mindfulness were associated with reduced self-care. Outcome (magnitude) sensitivity, a latent decision-making parameter derived from computationally modeling successive choices in a gambling task, was also associated with self-care behavior. These results are preliminary;more research is needed to demonstrate the utility of these findings in clinical settings. Information about associations between impulsivity and poor self-care in people with SCI could guide the development of interventions to improve SCI self-care and help patients with elevated risks related to self-care and secondary health conditions.

Prospects for the use of olfactory mucosa cells in bioprinting for the treatment of spinal cord injuries

The review focuses on the most important areas of cell therapy for spinal cord injuries.Olfactory mucosa cells are promising for transplantation.Obtaining these cells is safe for patients.The use of olfactory mucosa cells is effective in restoring motor function due to the remyelination and regeneration of axons after spinal cord injuries.These cells express neurotrophic factors that play an important role in the functional recovery of nerve tissue after spinal cord injuries.In addition,it is possible to increase the content of neurotrophic factors,at the site of injury,exogenously by the direct injection of neurotrophic factors or their delivery using gene therapy.The advantages of olfactory mucosa cells,in combination with neurotrophic factors,open up wide possibilities for their application in threedimensional and four-dimensional bioprinting technology treating spinal cord injuries.

Technical comments on rodent spinal cord injuries models

Spinal cord injuries （SCI） in rodents have been created by laceration, contusion, compression, or intramedullary injection of toxic agents. The choice of an appropriate SCI model should be made for each study based on the experimental design, with care taken to avoid unintended complications such as hemorrhage. Technical comments will be made in this communication describing the 1） importance of vertebral stabi- lization, 2） injury preparation, and 3） landmarks to improve the preci- sion and reproducibility of the SCI.

New insight into curcumin-based therapy in spinal cord injuries： CISD2 regulation

Multiple protective effects of curcumin in cases of spinal cord injuries（SCIs）：Curcumin[1,7-bis（4-hydroxy-3-methoxyphenyl）-1,6-heptadiene-3,5-dione]is a nonsteroidal,naturally occurring compound commonly utilized as a dietary pigment as well as a spice in India.It is obtained from curcuma longa in.

Clinical features of multiple trauma patients combined with spine and spinal cord injuries

Objective To analyze the clinical features of the multiple trauma patients combined with spine and spinal cord injuries.Methods A retrospective study was performed in143multiple trauma patients combined with spine and spinal

Acute complications of spinal cord injuries

The aim of this paper is to give an overview of acute complications of spinal cord injury(SCI). Along with motor and sensory deficits, instabilities of the cardiovascular, thermoregulatory and broncho-pulmonary system are common after a SCI. Disturbances of the urinary and gastrointestinal systems are typical as well as sexual dysfunction. Frequent complications of cervical and high thoracic SCI are neurogenic shock, bradyarrhythmias, hypotension, ectopic beats, abnormal temperaturecontrol and disturbance of sweating, vasodilatation and autonomic dysreflexia. Autonomic dysreflexia is an abrupt, uncontrolled sympathetic response, elicited by stimuli below the level of injury. The symptoms may be mild like skin rash or slight headache, but can cause severe hypertension, cerebral haemorrhage and death. All personnel caring for the patient should be able to recognize the symptoms and be able to intervene promptly. Disturbance of respiratory function are frequent in tetraplegia and a primary cause of both short and long-term morbidity and mortality is pulmonary complications. Due to physical inactivity and altered haemostasis, patients with SCI have a higher risk of venous thromboembolism and pressure ulcers. Spasticity and pain are frequent complications which need to be addressed. The psychological stress associated with SCI may lead to anxiety and depression. Knowledge of possible complications during the acute phase is important because they may be life threatening and/ or may lead to prolonged rehabilitation.

Stem cells for spinal cord injuries bearing translational potential

Spinal cord injury （SCI） is a highly debilitating neurological disease, which still lacks effective treatment strategies, causing significant financial burden and distress to the affected families. Nevertheless, nanotechnology and regenerative medicine strategies holding promise for the development of novel therapies that would reach from bench to bedside to serve the SCI patients. There has already been significant progress in the field of cell-based therapies, with the clinical application for SCI, currently in phase II of the clinical trial. Stem cells （e.g., induced pluripotent stem cells, fetal stem cells, human embryonic stem cells, and olfactory ensheathing cells） are certainly not to be considered the panacea for neural repair but, especially when combined with rehabilitation or other combinatorial approaches using the help of nanotechnology, they seem to be the source of some of the most promising and clinical translatable cell-based therapies that could help solving impactful problems on neural repair.

Apelin inhibits motor neuron apoptosis in the anterior horn following acute spinal cord and sciatic nerve injuries

Rat models of acute spinal cord injury and sciatic nerve injury were established. Apelin expression in spinal cord tissue was determined. In normal rat spinal cords, apelin expression was visible; however, 2 hours post spinal cord injury, apelin expression peaked. Apelin expression increased 1 day post ligation of the sciatic nerve compared with normal rat spinal cords, and peaked at 3 days. Apelin expression was greater in the posterior horn compared with the anterior horn at each time point when compared with the normal group. The onset of neuronal apoptosis was significantly delayed following injection of apelin protein at the stump of the sciatic nerve, and the number of apoptotic cells after injury was reduced when compared with normal spinal cords. Our results indicate that apelin is expressed in the normal spinal cord and central nervous system after peripheral nerve injury. Apelin protein can reduce motor neuron apoptosis in the spinal cord anterior horn and delay the onset of apoptosis.

Multifunctional biomimetic spinal cord: New approach to repair spinal cord injuries

The incidence of spinal cord injury(SCI) has been gradually increasing, and the treatment has troubled the medical field all the time. Primary and secondary injuries ultimately lead to nerve impulse conduction block. Microglia and astrocytes excessively accumulate and proliferate to form the glial scar. At present, to reduce the effect of glial scar on nerve regeneration is a hot spot in the research on the treatment of SCI. According to the preliminary experiments, we would like to provide a new bionic spinal cord to reduce the negative effect of glial scar on nerve regeneration. In this hypothesis we designed a new scaffold that combine the common advantage of acellular scaffold of spinal cord and thermosensitive gel, which could continue to release exogenous basic fibroblast growth factor(BFGF) in the spinal lesion area on the basis of BFGF modified thermosensitive gel. Meanwhile, the porosity, pore size and material of the gray matter and white matter regions were distinguished by an isolation layer, so as to induce the directed differentiation of cells into the defect site and promote regeneration of spinal cord tissue.

Spinal Cord Injuries without Visible Bone Lesions: Analysis of Four Consecutive Cases

Objectives: Interest of this study is to report four cases of spinal cord injuries without bone lesion. Evolution of the injured patients according to the initial clinic assessment at admission and the treatment performed are discussed. Materials and Methods: From January to December 2016, we performed a retrospective study at the Neurosurgery Department of Hospital General Grand Yoff of Dakar. Four patients were followed for spinal cord injury without visible bone lesions. We analyzed the clinical, radiological, therapeutic and evolutionary data. Trauma caused by stabbing was excluded. Results: In a year, 83 cases of spinal trauma with neurological deficit were hospitalized in the department. Among them, 4 had spinal cord injuries without visible bone lesions. The average age was 31.7 years with extremes ranging from 14 to 47 years. The sex ratio of male/female was 3. We have recorded 2 cases of road traffic accidents, 1 case of fall from height and 1 case of sports accident. On the neurological level, we found 3 cases of tetraplegia, and 1 brachial monoplegia. Computed tomography in all patients was normal. All of them benefited from magnetic resonance imaging that showed spinal cord injury. All patients were under conservative treatment. One patient fully recovered, two partially and one passed away. Conclusion: In presence of any post traumatic myelopathy case, the absence of disco-vertebral lesions should bring to mind the SCIWORA as well as indicate the realization of magnetic resonance imaging.

Evaluation of Patients Who Received Robotic Therapy after Spinal Cord Injuries

Background: This study aims to evaluate the effectiveness of the robotic device used in lower limb rehabilitation to reduce motor impairment and improve motor performance in patients with traumatic spinal injury. Methods: The data were obtained by retrospective analysis of patients who underwent lower extremity rehabilitation after traumatic spinal injury by robot-assisted rehabilitation in the hospital between December 2017 and December 2019. The results were statistically analyzed and shown as mean ± SD (min-max). Results: A total of 51 patients with mean age of 59.51 ± 8.2 (38 - 72) were admitted to the clinic. Mean ages of thirty-one male patients and twenty females patients were 58.74 ± 8.88 (38 - 77) and 60.7 ± 7.09 (44 - 72), respectively. Comparing ages in terms of gender, it was not statistically significant (p = 0.441). Body mass indexes of male patients were 32.84 ± 6.52 (20 - 48) and 31.4 ± 7.73 (18 - 48) for females. Body mass index of patients was not statistically significant in terms of their gender (p = 0.478). Oswestry disability index scores were 32.04 ± 10.74 (16 - 58) before treatment and 30.69 ± 10.31 (15 - 55) after treatment. Oswestry disability index values before and after robotic rehabilitation were statistically significant (p < 0.001). Significant improvement was observed in ASIA scale values after rehabilitation. Conclusions: The motor function gains obtained during the robot-assisted treatment of traumatic spinal injury patients showed robotic device was useful in the training program. Robotic rehabilitation was effective in the improvement of the lower extremities during motor examination.

Bromocriptine protects perilesional spinal cord neurons from lipotoxicity after spinal cord injury

Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity,damaging the neurons.However,how lipids are metabolized by spinal cord neurons after spinal cord injury remains unclear.Herein,we investigated lipid metabolism by spinal cord neurons after spinal cord injury and identified lipid-lowering compounds to treat spinal cord injury.We found that lipid droplets accumulated in perilesional spinal cord neurons after spinal cord injury in mice.Lipid droplet accumulation could be induced by myelin debris in HT22 cells.Myelin debris degradation by phospholipase led to massive free fatty acid production,which increased lipid droplet synthesis,β-oxidation,and oxidative phosphorylation.Excessive oxidative phosphorylation increased reactive oxygen species generation,which led to increased lipid peroxidation and HT22 cell apoptosis.Bromocriptine was identified as a lipid-lowering compound that inhibited phosphorylation of cytosolic phospholipase A2 by reducing the phosphorylation of extracellular signal-regulated kinases 1/2 in the mitogen-activated protein kinase pathway,thereby inhibiting myelin debris degradation by cytosolic phospholipase A2 and alleviating lipid droplet accumulation in myelin debris-treated HT22 cells.Motor function,lipid droplet accumulation in spinal cord neurons and neuronal survival were all improved in bromocriptine-treated mice after spinal cord injury.The results suggest that bromocriptine can protect neurons from lipotoxic damage after spinal cord injury via the extracellular signal-regulated kinases 1/2-cytosolic phospholipase A2 pathway.

Pharmacological interventions targeting the microcirculation following traumatic spinal cord injury

Traumatic spinal cord injury is a devastating disorder chara cterized by sensory,motor,and autonomic dysfunction that seve rely compromises an individual's ability to perform activities of daily living.These adve rse outcomes are closely related to the complex mechanism of spinal cord injury,the limited regenerative capacity of central neurons,and the inhibitory environment fo rmed by traumatic injury.Disruption to the microcirculation is an important pathophysiological mechanism of spinal cord injury.A number of therapeutic agents have been shown to improve the injury environment,mitigate secondary damage,and/or promote regeneration and repair.Among them,the spinal cord microcirculation has become an important target for the treatment of spinal cord injury.Drug inte rventions targeting the microcirculation can improve the microenvironment and promote recovery following spinal cord injury.These drugs target the structure and function of the spinal cord microcirculation and are essential for maintaining the normal function of spinal neuro ns,axons,and glial cells.This review discusses the pathophysiological role of spinal cord microcirculation in spinal cord injury,including its structure and histopathological changes.Further,it summarizes the progress of drug therapies targeting the spinal cord mic rocirc ulation after spinal cord injury.

In vivo imaging of the neuronal response to spinal cord injury:a narrative review

Deciphering the neuronal response to injury in the spinal cord is essential for exploring treatment strategies for spinal cord injury(SCI).However,this subject has been neglected in part because appropriate tools are lacking.Emerging in vivo imaging and labeling methods offer great potential for observing dynamic neural processes in the central nervous system in conditions of health and disease.This review first discusses in vivo imaging of the mouse spinal cord with a focus on the latest imaging techniques,and then analyzes the dynamic biological response of spinal cord sensory and motor neurons to SCI.We then summarize and compare the techniques behind these studies and clarify the advantages of in vivo imaging compared with traditional neuroscience examinations.Finally,we identify the challenges and possible solutions for spinal cord neuron imaging.

Progress in the generation of spinal cord organoids over the past decade and future perspectives

Spinal cord organoids are three-dimensional tissues derived from stem cells that recapitulate the primary morphological and functional characteristics of the spinal cord in vivo.As emerging bioengineering methods have led to the optimization of cell culture protocols,spinal cord organoids technology has made remarkable advancements in the past decade.Our literature search found that current spinal cord organoids do not only dynamically simulate neural tube formation but also exhibit diverse cytoarchitecture along the dorsal-ventral and rostral-caudal axes.Moreover,fused organoids that integrate motor neurons and other regionally specific organoids exhibit intricate neural circuits that allows for functional assessment.These qualities make spinal cord organoids valuable tools for disease modeling,drug screening,and tissue regeneration.By utilizing this emergent technology,researchers have made significant progress in investigating the pathogenesis and potential therapeutic targets of spinal cord diseases.However,at present,spinal cord organoid technology remains in its infancy and has not been widely applied in translational medicine.Establishment of the next generation of spinal cord organoids will depend on good manufacturing practice standards and needs to focus on diverse cell phenotypes and electrophysiological functionality evaluation.

WJSC 6^(th) Anniversary Special Issues(2):Mesenchymal stem cells Mesenchymal stem cells in the treatment of spinal cord injuries:A review

With technological advances in basic research,the intricate mechanism of secondary delayed spinal cord injury(SCI)continues to unravel at a rapid pace.However,despite our deeper understanding of the molecular changes occurring after initial insult to the spinal cord,the cure for paralysis remains elusive.Current treatment of SCI is limited to early administration of high dose steroids to mitigate the harmful effect of cord edema that occurs after SCI and to reduce the cascade of secondary delayed SCI.R ecent evident-based clinical studies have cast doubt on the clinical benefit of steroids in SCI and intense focus on stem cell-based therapy has yielded some encouraging results.An array of mesenchymal stem cells(MSCs)from various sources with novel and promising strategies are being developed to improve function after SCI.In this review,we briefly discuss the pathophysiology of spinal cord injuries and characteristics and the potential sources of MSCs that can be used in the treatment of SCI.We will discuss the progress of MSCs application in research,focusing on the neuroprotective properties of MSCs.Finally,we will discuss the results from preclinical and clinical trials involving stem cell-based therapy in SCI.

Rehabilitation of spinal cord injuries

Spinal cord injury(SCI) is the injury of the spinal cord from the foramen magnum to the cauda equina whichoccurs as a result of compulsion, incision or contusion. The most common causes of SCI in the world are traffic accidents, gunshot injuries, knife injuries, falls and sports injuries. There is a strong relationship between functional status and whether the injury is complete or not complete, as well as the level of the injury. The results of SCI bring not only damage to independence and physical function, but also include many complications from the injury. Neurogenic bladder and bowel, urinary tract infections, pressure ulcers, orthostatic hypotension, fractures, deep vein thrombosis, spasticity, autonomic dysreflexia, pulmonary and cardiovascular problems, and depressive disorders are frequent complications after SCI. SCI leads to serious disability in the patient resulting in the loss of work, which brings psychosocial and economic problems. The treatment and rehabilitation period is long, expensive and exhausting in SCI. Whether complete or incomplete, SCI rehabilitation is a long process that requires patience and motivation of the patient and relatives. Early rehabilitation is important to prevent joint contractures and the loss of muscle strength, conservation of bone density, and to ensure normal functioning of the respiratory and digestive system. An interdisciplinary approach is essential in rehabilitation in SCI, as in the other types of rehabilitation. The team is led by a physiatrist and consists of the patients' family, physiotherapist, occupational therapist, dietician, psychologist, speech therapist, social worker and other consultant specialists as necessary.

Current and future surgery strategies for spinal cord injuries

Spinal cord trauma is a prominent cause of mortality and morbidity. In developed countries a spinal cord injury(SCI) occurs every 16 min. SCI occurs due to tissue destruction, primarily by mechanical and secondarily ischemic. Primary damage occurs at the time of the injury. It cannot be improved. Following the primary injury, secondary harm mechanisms gradually result in neuronal death. One of the prominent causesof secondary harm is energy deficit, emerging from ischemia, whose main cause in the early stage, is impaired perfusion. Due to the advanced techniques in spinal surgery, SCI is still challenging for surgeons. Spinal cord doesn't have a self-repair property. The main damage occurs at the time of the injury primarily by mechanical factors that cannot be improved. Secondarily mechanisms take part in the following sections. Spinal compression and neurological deficit are two major factors used to decide on surgery. According to advanced imaging techniques the classifications systems for spinal injury has been changed in time. Aim of the surgery is to decompress the spinal channel and to restore the spinal alinement and mobilize the patient as soon as possible. Use of neuroprotective agents as well as methods to achieve cell regeneration in addition to surgery would contribute to the solution.

Effects of neural stem cell transplantation on the motor function of rats with contusion spinal cord injuries:a meta-analysis

Objective:To judge the efficacies of neural stem cell(NSC)transplantation on functional recovery following contusion spinal cord injuries(SCIs).Data sources:Studies in which NSCs were transplanted into a clinically relevant,standardized rat model of contusion SCI were identified by searching the PubMed,Embase and Cochrane databases,and the extracted data were analyzed by Stata 14.0.Data selection:Inclusion criteria were that NSCs were used in in vivo animal studies to treat contusion SCIs and that behavioral assessment of locomotor functional recovery was performed using the Basso,Beattie,and Bresnahan lo-comotor rating scale.Exclusion criteria included a follow-up of less than 4 weeks and the lack of control groups.Outcome measures:The restoration of motor function was assessed by the Basso,Beattie,and Bresnahan locomotor rating scale.Results:We identified 1756 non-duplicated papers by searching the aforementioned electronic databases,and 30 full-text articles met the inclusion criteria.A total of 37 studies reported in the 30 articles were included in the meta-analysis.The meta-analysis results showed that transplanted NSCs could improve the motor function recovery of rats following contusion SCIs,to a moderate extent(pooled standardized mean difference(SMD)=0.73;95%confidence interval(CI):0.47–1.00;P<0.001).NSCs obtained from different donor species(rat:SMD=0.74;95%CI:0.36–1.13;human:SMD=0.78;95%CI:0.31–1.25),at different donor ages(fetal:SMD=0.67;95%CI:0.43–0.92;adult:SMD=0.86;95%CI:0.50–1.22)and from different origins(brain-derived:SMD=0.59;95%CI:0.27–0.91;spinal cord-derived:SMD=0.51;95%CI:0.22–0.79)had similar efficacies on improved functional recovery;however,adult induced pluripotent stem cell-derived NSCs showed no significant efficacies.Furthermore,the use of higher doses of transplanted NSCs or the administration of immunosuppressive agents did not promote better locomotor function recovery(SMD=0.45;95%CI:0.21–0.70).However,shorter periods between the contusion induction and the NSC transplantation showed slightly higher efficacies(acute:SMD=1.22;95%CI:0.81–1.63;subacute:SMD=0.75;95%CI:0.42–1.09).For chronic injuries,NSC implantation did not significantly improve functional recovery(SMD=0.25;95%CI:–0.16 to 0.65).Conclusion:NSC transplantation alone appears to be a positive yet limited method for the treatment of contusion SCIs.