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

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.

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.

Pressure ulcers and acute risk factors in individuals with traumatic spinal fractures with or without spinal cord injuries:A prospective analysis of the National Spinal Column/Cord Injury Registry of Iran(NSCIR-IR)data

Purpose:To identify risk factors for developing pressure ulcers(PUs)in the acute care period of traumatic spinal fracture patients with or without spinal cord injuries(SCIs).Methods:Data were collected prospectively in participating the National Spinal column/Cord Injury Registry of Iran(NSCIR-IR)from individuals with traumatic spinal fractures with or without SCIs,in-clusive of the hospital stay from admission to discharge.Trained nursing staff examined the patients for the presence of PUs every 8 h during their hospital stay.The presence and grade of PUs were assessed according to the European Pressure Ulcer Advisory Panel classification.In addition to PU,following data were also extracted from the NSCIR-IR datasets during the period of 2015-2021:age,sex,Glasgow coma scale score at admission,having SCIs,marital status,surgery for a spinal fracture,American Spinal Injury Association impairment scale(AIS),urinary incontinence,level of education,admitted center,length of stay in the intensive care unit(ICU),hypertension,respiratory diseases,consumption of ciga-rettes,diabetes mellitus and length of stay in the hospital.Logistic regression models were used to es-timate the unadjusted and adjusted odds ratio(OR)with 95%confidence intervals(CI).Results:Altogether 2785 participants with traumatic spinal fractures were included.Among them,87(3.1%)developed PU during their hospital stay and 392(14.1%)had SCIs.In the SCI population,63(16.1%)developed PU during hospital stay.Univariate logistic regression for the whole sample showed that marital status,having SCIs,urinary incontinence,level of education,treating center,number of days in the ICU,age,and Glasgow coma scale score were significant predictors for PUs.However,further analysis by multiple logistic regression only revealed the significant risk factors to be the treating center,marital status,having SCIs,and the number of days in the ICU.For the subgroup of individuals with SCIs,marital status,AIS,urinary incontinence,level of education,the treating center,the number of days in the ICU and the number of days in the hospital were significant predictors for PUs by univariate analysis.After adjustment in the multivariate model,the treating center,marital status(singles vs.marrieds,OR=3.06,95%CI:1.55-6.03,p=0.001),and number of days in the ICU(OR=1.06,95%Cl:1.04-1.09,p<0.001)maintained significance.Conclusions:These data confirm that individuals with traumatic spinal fractures and SCIs,especially single young patients who suffer from urinary incontinence,grades A-D by AIS,prolonged ICU stay,and more extended hospitalization are at increased risk for PUs;as a result strategies to minimize PU development need further refinement.

Neurophysiological, histological, and behavioral characterization of animal models of distraction spinal cord injury: a systematic review

Distraction spinal cord injury is caused by some degree of distraction or longitudinal tension on the spinal cord and commonly occurs in patients who undergo corrective operation for severe spinal deformity.With the increased degree and duration of distraction,spinal cord injuries become more serious in terms of their neurophysiology,histology,and behavior.Very few studies have been published on the specific characteristics of distraction spinal cord injury.In this study,we systematically review 22 related studies involving animal models of distraction spinal cord injury,focusing particularly on the neurophysiological,histological,and behavioral characteristics of this disease.In addition,we summarize the mechanisms underlying primary and secondary injuries caused by distraction spinal cord injury and clarify the effects of different degrees and durations of distraction on the primary injuries associated with spinal cord injury.We provide new concepts for the establishment of a model of distraction spinal cord injury and related basic research,and provide reference guidelines for the clinical diagnosis and treatment of this disease.

Lupenone improves motor dysfunction in spinal cord injury mice through inhibiting the inflammasome activation and pyroptosis in microglia via the nuclear factor kappa B pathway

Spinal cord injury-induced motor dysfunction is associated with neuroinflammation.Studies have shown that the triterpenoid lupenone,a natural product found in various plants,has a remarkable anti-inflammatory effect in the context of chronic inflammation.However,the effects of lupenone on acute inflammation induced by spinal cord injury remain unknown.In this study,we established an impact-induced mouse model of spinal cord injury,and then treated the injured mice with lupenone(8 mg/kg,twice a day)by intrape ritoneal injection.We also treated BV2 cells with lipopolysaccharide and adenosine5’-triphosphate to simulate the inflammatory response after spinal cord injury.Our res ults showed that lupenone reduced IKBa activation and p65 nuclear translocation,inhibited NLRP3 inflammasome function by modulating nuclear factor kappa B,and enhanced the conve rsion of proinflammatory M1 mic roglial cells into anti-inflammatory M2 microglial cells.Furthermore,lupenone decreased NLRP3 inflammasome activation,NLRP3-induced mic roglial cell polarization,and microglia pyroptosis by inhibiting the nuclear factor kappa B pathway.These findings suggest that lupenone protects against spinal cord injury by inhibiting inflammasomes.

Epidemiological and clinical features,treatment status,and economic burden of traumatic spinal cord injury in China:a hospital-based retrospective study

Traumatic spinal cord injury is potentially catastrophic and can lead to permanent disability or even death.China has the largest population of patients with traumatic spinal cord injury.Previous studies of traumatic spinal cord injury in China have mostly been regional in scope;national-level studies have been rare.To the best of our knowledge,no national-level study of treatment status and economic burden has been performed.This retrospective study aimed to examine the epidemiological and clinical features,treatment status,and economic burden of traumatic spinal cord injury in China at the national level.We included 13,465 traumatic spinal cord injury patients who were injured between January 2013 and December 2018 and treated in 30 hospitals in 11 provinces/municipalities representing all geographical divisions of China.Patient epidemiological and clinical features,treatment status,and total and daily costs were recorded.Trends in the percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department and cost of care were assessed by annual percentage change using the Joinpoint Regression Program.The percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department did not significantly change overall(annual percentage change,-0.5%and 2.1%,respectively).A total of 10,053(74.7%)patients underwent surgery.Only 2.8%of patients who underwent surgery did so within 24 hours of injury.A total of 2005(14.9%)patients were treated with high-dose(≥500 mg)methylprednisolone sodium succinate/methylprednisolone(MPSS/MP);615(4.6%)received it within 8 hours.The total cost for acute traumatic spinal cord injury decreased over the study period(-4.7%),while daily cost did not significantly change(1.0%increase).Our findings indicate that public health initiatives should aim at improving hospitals’ability to complete early surgery within 24 hours,which is associated with improved sensorimotor recovery,increasing the awareness rate of clinical guidelines related to high-dose MPSS/MP to reduce the use of the treatment with insufficient evidence.

Photobiomodulation inhibits the expression of chondroitin sulfate proteoglycans after spinal cord injury via the Sox9 pathway

Both glial cells and glia scar greatly affect the development of spinal cord injury and have become hot spots in research on spinal cord injury treatment.The cellular deposition of dense extracellular matrix proteins such as chondroitin sulfate proteoglycans inside and around the glial scar is known to affect axonal growth and be a major obstacle to autogenous repair.These proteins are thus candidate targets for spinal cord injury therapy.Our previous studies demonstrated that 810 nm photo biomodulation inhibited the formation of chondroitin sulfate proteoglycans after spinal cord injury and greatly improved motor function in model animals.However,the specific mechanism and potential targets involved remain to be clarified.In this study,to investigate the therapeutic effect of photo biomodulation,we established a mouse model of spinal cord injury by T9 clamping and irradiated the injury site at a power density of 50 mW/cm~2 for 50 minutes once a day for 7 consecutive days.We found that photobiomodulation greatly restored motor function in mice and down regulated chondroitin sulfate proteoglycan expression in the injured spinal cord.Bioinformatics analysis revealed that photobiomodulation inhibited the expression of proteoglycan-related genes induced by spinal cord injury,and versican,a type of proteoglycan,was one of the most markedly changed molecules.Immunofluorescence staining showed that after spinal cord injury,versican was present in astrocytes in spinal cord tissue.The expression of versican in primary astrocytes cultured in vitro increased after inflammation induction,whereas photobiomodulation inhibited the expression of ve rsican.Furthermore,we found that the increased levels of p-Smad3,p-P38 and p-Erk in inflammatory astrocytes were reduced after photobiomodulation treatment and after delivery of inhibitors including FR 180204,(E)-SIS3,and SB 202190.This suggests that Sma d 3/Sox9 and MAP K/Sox9 pathways may be involved in the effects of photobiomodulation.In summary,our findings show that photobiomodulation modulates the expression of chondroitin sulfate proteoglycans,and versican is one of the key target molecules of photo biomodulation.MAPK/Sox9 and Smad3/Sox9 pathways may play a role in the effects of photo biomodulation on chondroitin sulfate proteoglycan accumulation after spinal cord injury.

Transplantation of fibrin-thrombin encapsulated human induced neural stem cells promotes functional recovery of spinal cord injury rats through modulation of the microenvironment

Recent studies have mostly focused on engraftment of cells at the lesioned spinal cord,with the expectation that differentiated neurons facilitate recovery.Only a few studies have attempted to use transplanted cells and/or biomaterials as major modulators of the spinal cord injury microenvironment.Here,we aimed to investigate the role of microenvironment modulation by cell graft on functional recovery after spinal cord injury.Induced neural stem cells reprogrammed from human peripheral blood mononuclear cells,and/or thrombin plus fibrinogen,were transplanted into the lesion site of an immunosuppressed rat spinal cord injury model.Basso,Beattie and Bresnahan score,electrophysiological function,and immunofluorescence/histological analyses showed that transplantation facilitates motor and electrophysiological function,reduces lesion volume,and promotes axonal neurofilament expression at the lesion core.Examination of the graft and niche components revealed that although the graft only survived for a relatively short period(up to 15 days),it still had a crucial impact on the microenvironment.Altogether,induced neural stem cells and human fibrin reduced the number of infiltrated immune cells,biased microglia towards a regenerative M2 phenotype,and changed the cytokine expression profile at the lesion site.Graft-induced changes of the microenvironment during the acute and subacute stages might have disrupted the inflammatory cascade chain reactions,which may have exerted a long-term impact on the functional recovery of spinal cord injury rats.

Biochanin A attenuates spinal cord injury in rats during early stages by inhibiting oxidative stress and inflammasome activation

Previous studies have shown that Biochanin A,a flavonoid compound with estrogenic effects,can serve as a neuroprotective agent in the context of cerebral ischemia/reperfusion injury;howeve r,its effect on spinal cord injury is still unclea r. In this study,a rat model of spinal cord injury was established using the heavy o bject impact method,and the rats were then treated with Biochanin A(40 mg/kg) via intrape ritoneal injection for 14 consecutive days.The res ults showed that Biochanin A effectively alleviated spinal cord neuronal injury and spinal co rd tissue injury,reduced inflammation and oxidative stress in spinal cord neuro ns,and reduced apoptosis and pyroptosis.In addition,Biochanin A inhibited the expression of inflammasome-related proteins(ASC,NLRP3,and GSDMD)and the Toll-like receptor 4/nuclear factor-κB pathway,activated the Nrf2/heme oxygenase 1 signaling pathway,and increased the expression of the autophagy markers LC3 Ⅱ,Beclin-1,and P62.Moreove r,the therapeutic effects of Biochanin A on early post-s pinal cord injury were similar to those of methylprednisolone.These findings suggest that Biochanin A protected neurons in the injured spinal cord through the Toll-like receptor 4/nuclear factor κB and Nrf2/heme oxygenase 1 signaling pathways.These findings suggest that Biochanin A can alleviate post-spinal cord injury at an early stage.

The future of artificial hibernation medicine:protection of nerves and organs after spinal cord injury

Spinal cord injury is a serious disease of the central nervous system involving irreversible nerve injury and various organ system injuries.At present,no effective clinical treatment exists.As one of the artificial hibernation techniques,mild hypothermia has preliminarily confirmed its clinical effect on spinal cord injury.However,its technical defects and barriers,along with serious clinical side effects,restrict its clinical application for spinal cord injury.Artificial hibernation is a futureoriented disruptive technology for human life support.It involves endogenous hibernation inducers and hibernation-related central neuromodulation that activate particular neurons,reduce the central constant temperature setting point,disrupt the normal constant body temperature,make the body adapt"to the external cold environment,and reduce the physiological resistance to cold stimulation.Thus,studying the artificial hibernation mechanism may help develop new treatment strategies more suitable for clinical use than the cooling method of mild hypothermia technology.This review introduces artificial hibernation technologies,including mild hypothermia technology,hibernation inducers,and hibernation-related central neuromodulation technology.It summarizes the relevant research on hypothermia and hibernation for organ and nerve protection.These studies show that artificial hibernation technologies have therapeutic significance on nerve injury after spinal co rd injury through inflammatory inhibition,immunosuppression,oxidative defense,and possible central protection.It also promotes the repair and protection of res pirato ry and digestive,cardiovascular,locomoto r,urinary,and endocrine systems.This review provides new insights for the clinical treatment of nerve and multiple organ protection after spinal cord injury thanks to artificial hibernation.At present,artificial hibernation technology is not mature,and research fa ces various challenges.Neve rtheless,the effort is wo rthwhile for the future development of medicine.

Resident immune responses to spinal cord injury:role of astrocytes and microglia

Spinal cord injury can be traumatic or non-traumatic in origin,with the latter rising in incidence and prevalence with the aging demographics of our society.Moreove r,as the global population ages,individuals with co-existent degenerative spinal pathology comprise a growing number of traumatic spinal cord injury cases,especially involving the cervical spinal cord.This makes recovery and treatment approaches particula rly challenging as age and comorbidities may limit regenerative capacity.For these reasons,it is critical to better understand the complex milieu of spinal cord injury lesion pathobiology and the ensuing inflammatory response.This review discusses microglia-specific purinergic and cytokine signaling pathways,as well as microglial modulation of synaptic stability and plasticity after injury.Further,we evaluate the role of astrocytes in neurotransmission and calcium signaling,as well as their border-forming response to neural lesions.Both the inflammatory and reparative roles of these cells have eluded our complete understanding and remain key therapeutic targets due to their extensive structural and functional roles in the nervous system.Recent advances have shed light on the roles of glia in neurotransmission and reparative injury responses that will change how interventions are directed.Understanding key processes and existing knowledge gaps will allow future research to effectively target these cells and harness their regenerative potential.

A comprehensive look at the psychoneuroimmunoendocrinology of spinal cord injury and its progression: mechanisms and clinical opportunities

Spinal cord injury(SCI)is a devastating and disabling medical condition generally caused by a traumatic event(primary injury).This initial trauma is accompanied by a set of biological mechanisms directed to ameliorate neural damage but also exacerbate initial damage(secondary injury).The alterations that occur in the spinal cord have not only local but also systemic consequences and virtually all organs and tissues of the body incur important changes after SCI,explaining the progression and detrimental consequences related to this condition.Psychoneuroimmunoendocrinology(PNIE)is a growing area of research aiming to integrate and explore the interactions among the different systems that compose the human organism,considering the mind and the body as a whole.The initial traumatic event and the consequent neurological disruption trigger immune,endocrine,and multisystem dysfunction,which in turn affect the patient's psyche and well-being.In the present review,we will explore the most important local and systemic consequences of SCI from a PNIE perspective,defining the changes occurring in each system and how all these mechanisms are interconnected.Finally,potential clinical approaches derived from this knowledge will also be collectively presented with the aim to develop integrative therapies to maximize the clinical management of these patients.

Advances in extracellular vesicle-based combination therapies for spinal cord injury

Spinal cord injury is a severe insult to the central nervous system that causes persisting neurological deficits.The currently available treatments involve surgical,medical,and rehabilitative strategies.However,none of these techniques can markedly reverse neurological deficits.Recently,extracellular vesicles from various cell sources have been applied to different models of spinal cord injury,thereby generating new cell-free therapies for the treatment of spinal cord injury.However,the use of extracellular vesicles alone is still associated with some notable shortcomings,such as their uncertainty in targeting damaged spinal cord tissues and inability to provide structural support to damaged axons.Therefore,this paper reviews the latest combined strategies for the use of extracellular vesicle-based technology for spinal cord injury,including the combination of extracellular vesicles with nanoparticles,exogenous drugs and/or biological scaffold materials,which facilitate the targeting ability of extracellular vesicles and the combinatorial effects with extracellular vesicles.We also highlight issues relating to the clinical transformation of these extracellular vesicle-based combination strategies for the treatment of spinal cord injury.

Conditioned medium from human dental pulp stem cells treats spinal cord injury by inhibiting microglial pyroptosis

Human dental pulp stem cell transplantation has been shown to be an effective therapeutic strategy for spinal cord injury.However,whether the human dental pulp stem cell secretome can contribute to functional recovery after spinal cord injury remains unclear.In the present study,we established a rat model of spinal cord injury based on impact injury from a dropped weight and then intraperitoneally injected the rats with conditioned medium from human dental pulp stem cells.We found that the conditioned medium effectively promoted the recovery of sensory and motor functions in rats with spinal cord injury,decreased expression of the microglial pyroptosis markers NLRP3,GSDMD,caspase-1,and interleukin-1β,promoted axonal and myelin regeneration,and inhibited the formation of glial scars.In addition,in a lipopolysaccharide-induced BV2 microglia model,conditioned medium from human dental pulp stem cells protected cells from pyroptosis by inhibiting the NLRP3/caspase-1/interleukin-1βpathway.These results indicate that conditioned medium from human dental pulp stem cells can reduce microglial pyroptosis by inhibiting the NLRP3/caspase-1/interleukin-1βpathway,thereby promoting the recovery of neurological function after spinal cord injury.Therefore,conditioned medium from human dental pulp stem cells may become an alternative therapy for spinal cord injury.