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Spinal cord injury (SCI) results in significant neural damage and inhibition of axonal regeneration due to an imbalanced microenvironment. Extensive evidence supports the efficacy of mesenchymal stem cell (MSC) transplantation as a therapeutic approach for SCI. This review aims to present an overview of MSC regulation on the imbalanced microenvironment following SCI, specifically focusing on inflammation, neurotrophy and axonal regeneration. The application, limitations and future prospects of MSC transplantation are discussed as well. Generally, a comprehensive perspective is provided for the clinical translation of MSC transplantation for SCI.

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In persons with a spinal cord injury (SCI), resistance training using neuromuscular electrical stimulation (NMES-RT) increases lean mass in the lower limbs. However, whether protein supplementation in conjunction with NMES-RT further enhances this training effect is unknown. In this randomized controlled pilot trial, 15 individuals with chronic SCI engaged in 3 times/week NMES-RT, with (NMES+PRO, n = 8) or without protein supplementation (NMES, n = 7), for 12 weeks. Before and after the intervention, whole body and regional body composition (DXA) and fasting glucose and insulin concentrations were assessed in plasma. Adherence to the intervention components was ≥96%. Thigh lean mass was increased to a greater extent after NMES+PRO compared to NMES (0.3 (0.2, 0.4) kg; p < 0.001). Furthermore, fasting insulin concentration and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) were decreased similarly in both groups (fasting insulin: 1 [-9, 11] pmol∙L-1; HOMA-IR: 0.1 [-0.3, 0.5] AU; both p ≥ 0.617). Twelve weeks of home-based NMES-RT increased thigh lean mass, an effect that was potentiated by protein supplementation. In combination with the excellent adherence and apparent improvement in cardiometabolic health outcomes, these findings support further investigation through a full-scale randomized controlled trial.

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Exercise training is a conventional treatment strategy throughout the entire treatment process for patients with spinal cord injury (SCI). Currently, exercise modalities for SCI patients primarily include aerobic exercise, endurance training, strength training, high-intensity interval training, and mind-body exercises. These exercises play a positive role in enhancing skeletal muscle function, inducing neuroprotection and regeneration, thereby influencing neural plasticity, reducing limb spasticity, and improving motor function and daily living abilities in SCI patients. However, the mechanism by which exercise training promotes functional recovery after SCI is still unclear, and there is no consensus on a unified and standardized exercise treatment plan. Different exercise methods may bring different benefits. After SCI, patients' physical activity levels decrease significantly due to factors such as motor dysfunction, which may be a key factor affecting changes in exerkines. The changes in exerkines of SCI patients caused by exercise training are an important and highly relevant and visual evaluation index, which may provide a new research direction for revealing the intrinsic mechanism by which exercise promotes functional recovery after SCI. Therefore, this article summarizes the changes in the expression of common exerkines (neurotrophic factors, inflammatory factors, myokines, bioactive peptides) after SCI, and intends to analyze the impact and role of different exercise methods on functional recovery after SCI from the perspective of exerkines mechanism. We hope to provide theoretical basis and data support for scientific exercise treatment programs after SCI.

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BACKGROUND: A spinal cord injury (SCI) can result in severe impairment and fatality as well as significant motor and sensory abnormalities. Exosomes produced from IPSCs have demonstrated therapeutic promise for accelerating spinal cord injury recovery, according to a recent study. OBJECTIVE: This study aims to develop engineered IPSCs-derived exosomes (iPSCs-Exo) capable of targeting and supporting neurons, and to assess their therapeutic potential in accelerating recovery from spinal cord injury (SCI). METHODS: iPSCs-Exo were characterized using Transmission Electron Microscopy (TEM), Nanoparticle Tracking Analysis (NTA), and western blot. To enhance neuronal targeting, iPSCs-Exo were bioengineered, and their uptake by neurons was visualized using PKH26 labeling and fluorescence microscopy. In vitro, the anti-inflammatory effects of miRNA-loaded engineered iPSCs-Exo were evaluated by exposing neurons to LPS and IFN-γ. In vivo, biodistribution of engineered iPSC-Exo was monitored using a vivo imaging system. The therapeutic efficacy of miRNA-loaded engineered iPSC-Exo in a SCI mouse model was assessed by Basso Mouse Scale (BMS) scores, H&E, and Luxol Fast Blue (LFB) staining. RESULTS: The results showed that engineered iPSC-Exo loaded with miRNA promoted the spinal cord injure recovery. Thorough safety assessments using H&E staining on major organs revealed no evidence of systemic toxicity, with normal organ histology and biochemistry profiles following engineered iPSC-Exo administration. CONCLUSION: These results suggest that modified iPSC-derived exosomes loaded with miRNA have great potential as a cutting-edge therapeutic approach to improve spinal cord injury recovery. The observed negligible systemic toxicity further underscores their potential safety and efficacy in clinical applications.

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AIMS: Spinal cord injuries (SCI) pose persistent challenges in clinical practice due to the secondary injury. Drawing from our experience in spinal cord fusion (SCF), we propose vascularized allogeneic spinal cord transplantation (vASCT) as a novel approach for SCI, much like organ transplantation has revolutionized organ failure treatment and vascularized composite-tissue allotransplantation has addressed limb defects. MATERIALS AND METHODS: In this study, 24 dogs were paired and underwent vASCT, with donor spinal cord grafts and polyethylene glycol (PEG) application for SCF. The experimental group (n = 8) received tacrolimus and methylprednisolone, while the control group (n = 4) received only methylprednisolone. Safety and efficacy of vASCT were evaluated through electrophysiology, imaging, and 6-month follow-up. RESULTS: The experimental group showed substantial recovery in hind limb motor function. Imaging revealed robust survival of spinal cord grafts and restoration of spinal cord continuity. In contrast, the control group maintained hind limb paralysis, with imaging confirming spinal cord graft necrosis and extensive defects. Electrophysiologically, the experimental group exhibited restored motor evoked potential signal conduction postoperatively, unlike the control group. Notably, PEG application during vASCT led to signal conduction recovery in intraoperative spinal cord evoked potential examinations for all dogs. CONCLUSION: In the vASCT surgical model, the combination of PEG with tacrolimus has demonstrated the ability to reconstruct spinal cord continuity and restore hind limb motor function in beagles. Notably, a low dose of tacrolimus has also exhibited an excellent anti-immune rejection effect. These findings highlight vASCT's potential promise as a therapeutic strategy for addressing irreversible SCI.

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Objective: To evaluate the leading challenges in developing countries' traumatic spinal cord injury (TSCI) care. Methods: We conducted a systematic search in electronic databases of PubMed, SCOPUS, Web of Science, EMBASE, and Cochrane Library on 16 April 2023. Studies that investigated challenges associated with the management of TSCI in developing countries were eligible for review. We extracted related outcomes and categorized them into four distinct parts: injury prevention, pre-hospital care, in-hospital care, and post-hospital care. Results: We identified 82 articles that met the eligibility criteria including 13 studies on injury prevention, 25 on pre-hospital care, 32 on in-hospital care, and 61 on post-hospital care. Challenges related to post-hospital problems including the personal, financial, and social consequences of patients' disabilities and the deficiencies in empowering people with TSCI were foremost studied. Lack of trained human resources, insufficient public education and delays in care delivery were barriers in the acute and chronic management of TSCI. A well-defined pre-hospital network and standard guidelines for the management of acute neurotrauma are needed. Critical challenges in injury prevention include deficiencies in infrastructure and supportive legislation. Conclusion: Studies focusing on injury prevention and pre-hospital care in TSCI management in developing countries warrant further investigation. It is imperative to develop systematic and evidence-based initiatives that are specifically tailored to the unique circumstances of each country to address these challenges effectively. By understanding the primary obstacles, policymakers and healthcare providers can establish goals for improving education, planning, legislation, and resource allocation.

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Introduction: 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. Methods: 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. 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%). Conclusion: 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.

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BACKGROUND: Spinal cord injury patients frequently suffer from anxiety and depression, which can seriously affect their quality of life and recovery. Acupuncture, as a traditional Chinese therapy, has been used to treat anxiety and depression for more than 2000 years. The aim is to evaluate the clinical efficacy of acupuncture in the treatment of anxiety and depression in spinal cord injury patients. METHODS: The literature on acupuncture treating anxiety and depression in patients with spinal cord injury in PubMed, Embase, Cochrane Library, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Chinese Scientific Journal Data, and Wanfang data were searched through computers from the establishment of the database to May 2024. In the study, the Cochrane tool for assessing the risk of bias was used and the meta-analyses were carried out using the software package Review Manager 5.4. RESULTS: Ten trials were included in this systematic review, with 361 cases in the experimental group and 355 cases in the control group. Meta-analysis showed that compared with conventional treatment, acupuncture combined with conventional treatment was beneficial in improving the total clinical efficacy (odds ratio = 3.55 [95% confidence interval {CI}: 1.34-9.37], P < .001). We found acupuncture-assisted therapy could be beneficial in improving the Modified Barthel Index (MD = 10.48 [95% CI: 4.78-16.19], P < .001) and reducing anxiety or depression scores (such as the Self-Rating Anxiety Scale [MD = -6.08 {95% CI: -6.85 to -5.30}, P < .001]; reducing the Self-Rating Depression Scale [MD = -6.01 {95% CI: -6.95 to -5.07}, P < .001]). In addition, the study showed that the application of acupuncture treatment could improve 5-hydroxytryptamine compared to control group (MD = 44.99 [95% CI: 40.04-49.95], P < .001) and reduce TNF-α compared to control group (MD = -7.78 [95% CI: -8.73 to -6.83], P < .001). CONCLUSION: Acupuncture could be used as a complementary therapy to reduce anxiety and depression in spinal cord injury patients. Further original and high-quality research is needed to verify the conclusions of this study.

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Patients with spinal cord injury (SCI) have permanent devastating motor and sensory disabilities. Secondary SCI is known for its complex progression and presents with sophisticated aberrant inflammation, vascular changes, and secondary cellular dysfunction, which aggravate the primary damage. Since their initial discovery, the potent neuroprotective effects and powerful delivery abilities of exosomes (Exos) have been reported in different research fields, including SCI. In this study, we summarize therapeutic advances related to the application of Exos in preclinical animal studies. Subsequently, we discuss the mechanisms of action of Exos derived from diverse cell types, including neurogenesis, angiogenesis, blood-spinal cord barrier preservation, anti-apoptosis, and anti-inflammatory potential. We also evaluate the relationship between the Exo delivery cargo and signaling pathways. Finally, we discuss the challenges and advantages of using Exos to offer innovative insights regarding the development of efficient clinical strategies for SCI.

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People with a spinal cord injury are at an increased risk of metabolic dysfunction due to skeletal muscle atrophy and the transition of paralyzed muscle to a glycolytic, insulin-resistant phenotype. Providing doses of exercise through electrical muscle stimulation may provide a therapeutic intervention to help restore metabolic function for people with a spinal cord injury, but high-frequency and high-force electrically induced muscle contractions increase fracture risk for the underlying osteoporotic skeletal system. Therefore, we investigated the acute molecular responses after a session of either a 3 Hz or 1 Hz electrically induced exercise program. Ten people with a complete spinal cord injury completed a 1 h (3 Hz) or 3 h (1 Hz) unilateral electrically induced exercise session prior to a skeletal muscle biopsy of the vastus lateralis. The number of pulses was held constant. Tissue samples were analyzed for genomic and epigenomic expression profiles. There was a strong acute response after the 3 Hz exercise leading to the upregulation of early response genes (NR4A3, PGC-1α, ABRA, IRS2, EGR1, ANKRD1, and MYC), which have prominent roles in regulating molecular pathways that control mitochondrial biogenesis, contractile protein synthesis, and metabolism. Additionally, these genes, and others, contributed to the enrichment of pathways associated with signal transduction, cellular response to stimuli, gene expression, and metabolism. While there were similar trends observed after the 1 Hz exercise, the magnitude of gene expression changes did not reach our significance thresholds, despite a constant number of stimuli delivered. There were also no robust acute changes in muscle methylation after either form of exercise. Taken together, this study supports that a dose of low-force electrically induced exercise for 1 h using a 3 Hz stimulation frequency is suitable to trigger an acute genomic response in people with chronic paralysis, consistent with an expression signature thought to improve the metabolic and contractile phenotype of paralyzed muscle, if performed on a regular basis.

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Traumatic spinal cord injury (SCI) may occur across the lifespan and is of global relevance. Damage of the spinal cord results in para- or tetraplegia and is associated with neuropathic pain, spasticity, respiratory, and autonomic dysfunction (i.e., control of bladder-bowel function). While the acute surgical treatment aims at stabilizing the spine and decompressing the damaged spinal cord, SCI patients require neurorehabilitation to restore neural function and to compensate for any impairments including motor disability, pain treatment, and bladder/bowel management. However, the spinal cord has a limited capacity to regenerate and much of the disability may persist, depending on the initial lesion severity and level of injury. For this reason, and the lack of effective drug treatments, there is an emerging interest and urgent need in promoting axonal regeneration and remyelination after SCI through cell- and stem-cell based therapies. This review briefly summarizes the state-of the art management of acute SCI and its neurorehabilitation to critically appraise phase I/II trials from the last two decades that have investigated cell-based therapies (i.e., Schwann cells, macrophages, and olfactory ensheathing cells) and stem cell-based therapies (i.e., neural stem cells, mesenchymal, and hematopoietic stem cells). Recently, two large multicenter trials provided evidence for the safety and feasibility of neural stem cell transplantation into the injured cord, whilst two monocenter trials also showed this to be the case for the transplantation of Schwann cells into the posttraumatic cord cavity. These are milestone studies that will facilitate further interventional trials. However, the clinical adoption of such approaches remains unproven, as there is only limited encouraging data, often in single patients, and no proven trial evidence to support regulatory approval.

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This study aims to investigate the effect of adipose-derived stem cells (ADSCs) transplantation on progranulin (PGRN) expression and functional recovery in rats with spinal cord injury (SCI). ADSCs were isolated from the inguinal adipose tissue of rats. A SCI model was created, and ADSCs were injected into the injured area. Various techniques were used to assess the effects of ADSCs transplantation, including hematoxylin-eosin staining, Masson staining, immunofluorescence staining, electron microscopy, MRI, and motor function assessment. The potential mechanisms of ADSC transplantation were investigated using gene expression analysis and protein analysis. Finally, the safety of this therapy was evaluated through hematoxylin-eosin staining and indicators of liver and kidney damage in serum. PGRN expression increased in the injured spinal cord, and ADSCs transplantation further enhanced PGRN levels. The group that received ADSCs transplantation showed reduced inflammation, decreased scar formation, increased nerve regeneration, and faster recovery of bladder function. Importantly, motor function significantly improved in the ADSC transplantation group. ADSCs transplantation enhances functional regeneration in SCI by upregulating PGRN expression, reducing inflammation and scar formation, and promoting nerve regeneration and myelin repair. These findings suggest that ADSC transplantation is a potential therapy for SCI.

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Spinal cord injury (SCI) is a severe central nervous system disorder with no currently available effective treatment. Microglia are immune cells in the central nervous system that play crucial roles in the SCI occurrence, development, and recovery stages. They exhibit dynamic polarization over time and can switch between classical activation (M1) and alternative activation (M2) phenotypes to respond to environmental stimuli. The M1 phenotype is involved in initiating and sustaining inflammatory responses, while the M2 phenotype exerts anti-inflammatory effects and promotes tissue repair in damaged areas. Inhibiting M1 polarization and promoting M2 polarization have become hotspots in regulating neuroinflammation and treating SCI. This article provides a comprehensive review centered on modulating microglial polarization phenotypes for SCI treatment.

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Spinal cord injury (SCI) is a serious condition accompanied by severe adverse events that affect several aspects of the patient's life, such as motor, sensory, and functional impairment. Despite its severe consequences, definitive treatment for these injuries is still missing. Therefore, researchers have focused on developing treatment strategies aimed at ensuring full recovery post-SCI. Accordingly, attention has been drawn toward cellular therapy using mesenchymal stem cells. Considering their wide availability, decreased immunogenicity, wide expansion capacity, and impressive effectiveness in many therapeutic approaches, adipose-derived stem cell (ADSC) injections in SCI cases have been investigated and showed promising results. In this review, SCI pathophysiology and ADSC transplantation benefits are discussed independently, together with SCI animal models and adipose stem cell preparation and application techniques. The mechanisms of healing in an SCI post-ADSC injection, the outcomes of this therapeutic approach, and current clinical trials are also deliberated, in addition to the challenges and future perspectives, aiming to encourage further research in this field.

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Spinal cord injury (SCI) is a catastrophic condition that disrupts neurons within the spinal cord, leading to severe motor and sensory deficits. While current treatments can alleviate pain, they do not promote neural regeneration or functional recovery. Three-dimensional (3D) bioprinting offers promising solutions for SCI repair by enabling the creation of complex neural tissue constructs. This review provides a comprehensive overview of 3D bioprinting techniques, bioinks, and stem cell applications in SCI repair. Additionally, it highlights recent advancements in 3D bioprinted scaffolds, including the integration of conductive materials, the incorporation of bioactive molecules like neurotrophic factors, drugs, and exosomes, and the design of innovative structures such as multi-channel and axial scaffolds. These innovative strategies in 3D bioprinting can offer a comprehensive approach to optimizing the spinal cord microenvironment, advancing SCI repair. This review highlights a comprehensive understanding of the current state of 3D bioprinting in SCI repair, offering insights into future directions in the field of regenerative medicine.

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OBJECTIVE: To observe the efficacy of pelvic floor muscle training combined with electroacupuncture (EA) for bladder dysfunction after incomplete spinal cord injury (SCI). METHODS: Ninety patients with bladder dysfunction after incomplete SCI were randomly divided into an EA group (30 cases), a pelvic floor muscle training group (30 cases, 1 case dropped out), and a combined group (30 cases, 1 case dropped out). All groups received routine rehabilitation. The EA group received EA at Zhongji (CV 3), Guanyuan (CV 4), Mingmen (GV 4), Yaoyangguan (GV 3), bilateral Shenshu (BL 23), Ciliao (BL 32), and Pangguangshu (BL 28), with continuous waves at frequency of 100 Hz, and the needles were retained for 30 min, once daily, 6 times a week for 6 weeks. The pelvic floor muscle training group underwent pelvic floor muscle training two times a day, for 6 weeks. The combined group received both EA and pelvic floor muscle training. The daily average number of urinations, daily average number of urinary leakages, urodynamic indexes (residual urine volume, maximum bladder capacity, bladder compliance, and maximum urine flow rate), and generic quality of life inventory-74 (GQOLI-74) were compared before and after treatment in each group. RESULTS: Compared before treatment, the daily average number of urinations and urinary leakages were decreased (P<0.05), residual urine volume, maximum bladder capacity, and bladder compliance were reduced (P<0.05), and maximum urine flow rate and GQOLI-74 scores were increased (P<0.05) after treatment in all groups. After treatment, the combined group showed greater differences in the daily average number of urinations, daily average number of urinary leakages, residual urine volume, maximum bladder capacity, bladder compliance, maximum urine flow rate, and GQOLI-74 score compared to the EA group and the pelvic floor muscle training group (P<0.05). There was no statistically significant differences in the changes in these indexes between the EA group and the pelvic floor muscle training group (P>0.05). CONCLUSION: Pelvic floor muscle training combined with EA can effectively alleviate urination problems in patients with bladder dysfunction after incomplete SCI, improve bladder function, and enhance patients' quality of life.

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OBJECTIVE: To determine frequency that ED visits are needed, and the most common chief complaints and medications prescribed to Veterans with spinal cord injuries and disorders (SCI/D). METHODS: The Veterans Health Administration (VHA) SCI and Disorders (SCI/D) Registry (VHA SCIDR) was used to identify Veterans with SCI/D over a five-year period (fiscal years 2018-2022). The primary outcome was the proportion of Veterans with SCI/D who had visits to the ED during the study period. Secondary outcomes included diagnostic codes and medications prescribed in the ED, and other healthcare encounters. RESULTS: Overall, 18,464 Veterans with SCI/D, including 80,661 patient-years were included. Of these Veterans, 10,234 (55.4%) had at least one ED visit and 8230 (44.6%) did not. ED visits were consistent, ranging from 33.5% to 36.4% annually. The number of in-person healthcare encounters decreased over the study period. The most common ED diagnostic codes were paraplegia or quadriplegia, discharge counseling, UTI, neuromuscular dysfunction of the bladder and low back pain. The most common medications prescribed in the ED were analgesics (e.g., acetaminophen, ketorolac), antimicrobials (e.g., ceftriaxone, vancomycin) and ondansetron. Antibiotics were among the most prescribed discharge medications, including ciprofloxacin, sulfamethoxazole/trimethoprim, cephalexin, and doxycycline. CONCLUSION: This national study of Veterans with SCI/D characterized ED healthcare utilization. Overall, more than half of Veterans with SCI/D required an ED visit during the five-year study period and over one third of Veterans in each fiscal year required an ED visit. Interventions to target prevention of ED visits and subsequent hospitalizations could focus on these areas.

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