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.

Epidemiological characteristics of traumatic spinal cord injuries in the intensive care unit from 2018 to 2023:a retrospective hospital-based study

BACKGROUND:The objective of this retrospective hospital-based study was to describe the epidemiological features of traumatic spinal cord injury(TSCI)in the intensive care unit(ICU)and assess the incidence and possible risk factors for venous thromboembolism(VTE)following TSCI.METHODS:We retrospectively reviewed the medical records of 370 patients with TSCI who were admitted between January 2018 and March 2023.The following parameters were collected:age,sex,body mass index,occupation,underlying diseases,smoking history,education level,etiology of injury,injury segments,American Spinal Injury Association(ASIA)Impairment Scale score,severity of injury,injury severity score(ISS),VTE risk score(Caprini score),treatment,VTE prophylaxis,ICU length of stay,length of hospital stay,concomitant injuries,and complications.Descriptive statistics were used to summarize the demographic and clinical characteristics of the study participants.Logistic regression analysis was used to determine the risk factors for VTE.RESULTS:The mean age of patients with TSCI was 55.5±13.4 years,with a male-to-female ratio of 6.5:1.The leading cause of TSCI was falls from height(46.5%),followed by traffic accidents(36.5%).The cervical spinal cord was the most affected segment,followed by the thoracolumbar region.Among all the patients,362(97.8%)had concomitant injuries.Complications were observed in 255 patients(68.9%)during hospitalization.The incidence rate of VTE was 25.1%.Logistic regression analysis revealed that age(OR=1.721,95%CI:1.207-2.454,P=0.003),mechanical ventilation(OR=3.427,95%CI:1.873-6.271,P<0.001),and non-use of chemical prophylaxis(OR=2.986,95%CI:1.749-5.099,P<0.001)were risk factors for VTE.CONCLUSION:Falls from height and traffic accidents were the main causes of TSCIs in the ICU,especially for male patients with cervical spinal cord injuries.VTE is a frequent complication in patients with TSCI in the ICU.Age,mechanical ventilation,and non-use of chemical prophylaxis were found to be independent risk factors for VTE following TSCI.

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.

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.

Sacral anterior root stimulated defecation in spinal cord injuries: An experimental study in canine model

AIM: To investigate whether there was a dominant sacral root for the motive function of rectum and anal sphincter, and to provide an experimental basis for sacral root electrically stimulated defecation in spinal cord injuries. METHODS: Eleven spinal cord injured mongrel dogs were included in the study. After L4-L7 laminectomy, the bilateral L7-S3 roots were electrostimulated separately and rectal and sphincter pressure were recorded synchronously. Four animals were implanted electrodes on bilateral S2 roots. RESULTS: For rectal motorial innervation, S2 was the most dominant (mean 15.2 kPa, 37.7% of total pressure), S1(11.3 kPa, 27.6%) and S3 (10.9 kPa, 26.7%) contributed to a smaller part. For external anal sphincter, S3 (mean 17.2 kPa, 33.7%) was the most dominant, S2 (16.2 kPa, 31.6%) and S1(14.3 kPa, 27.9%) contributed to a lesser but still a significant part. Above 85% L7 roots provided some functional contribution to rectum and anal sphincter. For both rectum and sphincter, the right sacral roots provided more contribution than the left roots. Postoperatively, the 4 dogs had electrically stimulated defecation and micturition under the control of the neuroprosthetic device. CONCLUSION: S2 root is the most dominant contributor to rectal pressure in dogs. Stimulation of bilateral S2 with implanted electrodes contributes to good micturition and defecation in dogs.

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.

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.

Metabolic reprogramming: a new option for the treatment of spinal cord injury

Spinal cord injuries impose a notably economic burden on society,mainly because of the severe after-effects they cause.Despite the ongoing development of various therapies for spinal cord injuries,their effectiveness remains unsatisfactory.However,a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic reprogramming.In this review,we explore the metabolic changes that occur during spinal cord injuries,their consequences,and the therapeutic tools available for metabolic reprogramming.Normal spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic coupling.However,spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism,lipid metabolism,and mitochondrial dysfunction.These metabolic disturbances lead to corresponding pathological changes,including the failure of axonal regeneration,the accumulation of scarring,and the activation of microglia.To rescue spinal cord injury at the metabolic level,potential metabolic reprogramming approaches have emerged,including replenishing metabolic substrates,reconstituting metabolic couplings,and targeting mitochondrial therapies to alter cell fate.The available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord injury.To further advance the metabolic treatment of the spinal cord injury,future efforts should focus on a deeper understanding of neurometabolism,the development of more advanced metabolomics technologies,and the design of highly effective metabolic interventions.

Mutual regulation of microglia and astrocytes after Gas6 inhibits spinal cord injury

Invasive inflammation and excessive scar formation are the main reasons for the difficulty in repairing nervous tissue after spinal cord injury.Microglia and astrocytes play key roles in the spinal cord injury micro-environment and share a close interaction.However,the mechanisms involved remain unclear.In this study,we found that after spinal cord injury,resting microglia(M0)were polarized into pro-inflammatory phenotypes(MG1 and MG3),while resting astrocytes were polarized into reactive and scar-forming phenotypes.The expression of growth arrest-specific 6(Gas6)and its receptor Axl were significantly down-regulated in microglia and astrocytes after spinal cord injury.In vitro experiments showed that Gas6 had negative effects on the polarization of reactive astrocytes and pro-inflammatory microglia,and even inhibited the cross-regulation between them.We further demonstrated that Gas6 can inhibit the polarization of reactive astrocytes by suppressing the activation of the Yes-associated protein signaling pathway.This,in turn,inhibited the polarization of pro-inflammatory microglia by suppressing the activation of the nuclear factor-κB/p65 and Janus kinase/signal transducer and activator of transcription signaling pathways.In vivo experiments showed that Gas6 inhibited the polarization of pro-inflammatory microglia and reactive astrocytes in the injured spinal cord,thereby promoting tissue repair and motor function recovery.Overall,Gas6 may play a role in the treatment of spinal cord injury.It can inhibit the inflammatory pathway of microglia and polarization of astrocytes,attenuate the interaction between microglia and astrocytes in the inflammatory microenvironment,and thereby alleviate local inflammation and reduce scar formation in the spinal cord.

Nanoparticles for the treatment of spinal cord injury

Spinal cord injuries lead to significant loss of motor, sensory, and autonomic functions, presenting major challenges in neural regeneration. Achieving effective therapeutic concentrations at injury sites has been a slow process, partly due to the difficulty of delivering drugs effectively. Nanoparticles, with their targeted delivery capabilities, biocompatibility, and enhanced bioavailability over conventional drugs, are garnering attention for spinal cord injury treatment. This review explores the current mechanisms and shortcomings of existing treatments, highlighting the benefits and progress of nanoparticle-based approaches. We detail nanoparticle delivery methods for spinal cord injury, including local and intravenous injections, oral delivery, and biomaterial-assisted implantation, alongside strategies such as drug loading and surface modification. The discussion extends to how nanoparticles aid in reducing oxidative stress, dampening inflammation, fostering neural regeneration, and promoting angiogenesis. We summarize the use of various types of nanoparticles for treating spinal cord injuries, including metallic, polymeric, protein-based, inorganic non-metallic, and lipid nanoparticles. We also discuss the challenges faced, such as biosafety, effectiveness in humans, precise dosage control, standardization of production and characterization, immune responses, and targeted delivery in vivo. Additionally, we explore future directions, such as improving biosafety, standardizing manufacturing and characterization processes, and advancing human trials. Nanoparticles have shown considerable progress in targeted delivery and enhancing treatment efficacy for spinal cord injuries, presenting significant potential for clinical use and drug development.

Pyroptosis,ferroptosis,and autophagy in spinal cord injury:regulatory mechanisms and therapeutic targets

Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.

Chondroitinase ABC combined with Schwann cell transplantation enhances restoration of neural connection and functional recovery following acute and chronic spinal cord injury

Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury.A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity,and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar,thus limiting axonal reentry into the host spinal cord.Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury.We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders,Schwann cells migrated for considerable distances in both rostral and caudal directions.Such Schwann cell migration led to enhanced axonal regrowth,including the serotonergic and dopaminergic axons originating from supraspinal regions,and promoted recovery of locomotor and urinary bladder functions.Importantly,the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury,even when treatment was delayed for 3 months to mimic chronic spinal cord injury.These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury.

Microglia:a promising therapeutic target in spinal cord injury

Microglia are present throughout the central nervous system and are vital in neural repair,nutrition,phagocytosis,immunological regulation,and maintaining neuronal function.In a healthy spinal cord,microglia are accountable for immune surveillance,however,when a spinal cord injury occurs,the microenvironment drastically changes,leading to glial scars and failed axonal regeneration.In this context,microglia vary their gene and protein expression during activation,and proliferation in reaction to the injury,influencing injury responses both favorably and unfavorably.A dynamic and multifaceted injury response is mediated by microglia,which interact directly with neurons,astrocytes,oligodendrocytes,and neural stem/progenitor cells.Despite a clear understanding of their essential nature and origin,the mechanisms of action and new functions of microglia in spinal cord injury require extensive research.This review summarizes current studies on microglial genesis,physiological function,and pathological state,highlights their crucial roles in spinal cord injury,and proposes microglia as a therapeutic target.

Pharmacological targeting cGAS/STING/NF-κB axis by tryptanthrin induces microglia polarization toward M2 phenotype and promotes functional recovery in a mouse model of spinal cord injury

The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury.Regulation of shifting microglia polarization from M1(neurotoxic and proinflammatory type)to M2(neuroprotective and anti-inflammatory type)after spinal cord injury appears to be crucial.Tryptanthrin possesses an anti-inflammatory biological function.However,its roles and the underlying molecular mechanisms in spinal cord injury remain unknown.In this study,we found that tryptanthrin inhibited microglia-derived inflammation by promoting polarization to the M2 phenotype in vitro.Tryptanthrin promoted M2 polarization through inactivating the cGAS/STING/NF-κB pathway.Additionally,we found that targeting the cGAS/STING/NF-κB pathway with tryptanthrin shifted microglia from the M1 to M2 phenotype after spinal cord injury,inhibited neuronal loss,and promoted tissue repair and functional recovery in a mouse model of spinal cord injury.Finally,using a conditional co-culture system,we found that microglia treated with tryptanthrin suppressed endoplasmic reticulum stress-related neuronal apoptosis.Taken together,these results suggest that by targeting the cGAS/STING/NF-κB axis,tryptanthrin attenuates microglia-derived neuroinflammation and promotes functional recovery after spinal cord injury through shifting microglia polarization to the M2 phenotype.

Treatment of spinal cord injury with biomaterials and stem cell therapy in non-human primates and humans

Spinal cord injury results in the loss of sensory,motor,and autonomic functions,which almost always produces permanent physical disability.Thus,in the search for more effective treatments than those already applied for years,which are not entirely efficient,researches have been able to demonstrate the potential of biological strategies using biomaterials to tissue manufacturing through bioengineering and stem cell therapy as a neuroregenerative approach,seeking to promote neuronal recovery after spinal cord injury.Each of these strategies has been developed and meticulously evaluated in several animal models with the aim of analyzing the potential of interventions for neuronal repair and,consequently,boosting functional recovery.Although the majority of experimental research has been conducted in rodents,there is increasing recognition of the importance,and need,of evaluating the safety and efficacy of these interventions in non-human primates before moving to clinical trials involving therapies potentially promising in humans.This article is a literature review from databases(PubMed,Science Direct,Elsevier,Scielo,Redalyc,Cochrane,and NCBI)from 10 years ago to date,using keywords(spinal cord injury,cell therapy,non-human primates,humans,and bioengineering in spinal cord injury).From 110 retrieved articles,after two selection rounds based on inclusion and exclusion criteria,21 articles were analyzed.Thus,this review arises from the need to recognize the experimental therapeutic advances applied in non-human primates and even humans,aimed at deepening these strategies and identifying the advantages and influence of the results on extrapolation for clinical applicability in humans.

Complement-dependent neuroinflammation in spinal cord injury:from pathology to therapeutic implications

Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this population.Following the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing research.In this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the pathology.We study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular patterns.Several effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord injury.Following this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human subjects.This review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.

Inhibiting SHP2 reduces glycolysis, promotes microglial M1 polarization, and alleviates secondary inflammation following spinal cord injury in a mouse model

Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2(SHP2), encoded by PTPN11, is widely expressed in the human body and plays a role in inflammation through various mechanisms. Therefore, SHP2 is considered a potential target for the treatment of inflammation-related diseases. However, its role in secondary inflammation after spinal cord injury remains unclear. In this study, SHP2 was found to be abundantly expressed in microglia at the site of spinal cord injury. Inhibition of SHP2 expression using siRNA and SHP2 inhibitors attenuated the microglial inflammatory response in an in vitro lipopolysaccharide-induced model of inflammation. Notably, after treatment with SHP2 inhibitors, mice with spinal cord injury exhibited significantly improved hind limb locomotor function and reduced residual urine volume in the bladder. Subsequent in vitro experiments showed that, in microglia stimulated with lipopolysaccharide, inhibiting SHP2 expression promoted M2 polarization and inhibited M1 polarization. Finally, a co-culture experiment was conducted to assess the effect of microglia treated with SHP2 inhibitors on neuronal cells. The results demonstrated that inflammatory factors produced by microglia promoted neuronal apoptosis, while inhibiting SHP2 expression mitigated these effects. Collectively, our findings suggest that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. Therefore, inhibiting SHP2 alleviates the inflammatory response in mice with spinal cord injury and promotes functional recovery postinjury.