Spinal Cord Injury Lesion Research Articles

Non-resolving neuroinflammation regulates axon regeneration in chronic spinal cord injury.

Chronic spinal cord injury (SCI) lesions retain increased densities of microglia and macrophages. In acute SCI, macrophages induce growth cone collapse and facilitate axon retraction away from lesion boundaries. Little is known about the role of sustained inflammation in chronic SCI, or whether chronic inflammation affects regeneration. We used the CSF1R inhibitor, PLX-5622, to deplete microglia and macrophages months after complete crush SCI in female mice. Transcriptional analyses revealed a significant inflammatory depletion within chronic SCI lesions after PLX-5622 treatment. Both transcriptional analyses and immunohistochemistry revealed that Iba1+ cells repopulate to pre-depleted densities after treatment removal. Neuronal-enriched transcripts were significantly elevated in mice after inflammatory repopulation, but no significant effects were observed with inflammatory depletion alone. Axon densities also significantly increased within the lesion after PLX-5622 treatment and after repopulation. To better examine the effect of chronic inflammation on axon regeneration, we tested PLX-5622 treatment in neuronal-specific PTEN knockout (PTEN-KO) mice. PTEN-KO was delivered using spinal injections of retrogradely transported adeno-associated viruses (AAVrg's). PTEN-KO did not further increase axon densities within the lesion beyond effects induced by PLX-5622. Axons that grew within the lesion were histologically identified as 5-HT+ and CGRP+, both of which are not robustly transduced by AAVrg's. Our work identified that increased macrophage/microglia densities in the chronic SCI environment may be actively retained by homeostatic mechanisms likely affiliated with a sustained elevated expression of CSF1 and other chemokines. Finally, we identify a novel role of sustained inflammation as a prospective barrier to axon regeneration in chronic SCI.Significance Statement Inflammatory macrophages infiltrate the spinal cord after a spinal cord injury (SCI) and remain at elevated densities around the lesion chronically. Little is known about the consequences of sustained spinal inflammation in chronic SCI, but it is known that macrophages impair regeneration early after SCI. We hypothesized that persistent neuroinflammation may function as a sustained barrier that chronically impairs axon regeneration. Our work identifies that the chronic SCI environment actively maintains increased densities of macrophages and implicates sustained inflammation as a persistent barrier to repair. Findings from our work change our understanding of the maintenance of non-resolving inflammation in chronic SCI and identifies a need to focus on overcoming chronic inflammatory barriers that limit repair after neurotrauma.

SCIseg: Automatic Segmentation of Intramedullary Lesions in Spinal Cord Injury on T2-weighted MRI Scans.

"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology: Artificial Intelligence. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content. Purpose To develop a deep learning tool for the automatic segmentation of the spinal cord and intramedullary lesions in spinal cord injury (SCI) on T2-weighted MRI scans. Materials and Methods This retrospective study included MRI data acquired between July 2002 and February 2023 from 191 patients with SCI (mean age, 48.1 years ± 17.9 [SD]; 142 males). The data consisted of T2-weighted MRI acquired using different scanner manufacturers with various image resolutions (isotropic and anisotropic) and orientations (axial and sagittal). Patients had different lesion etiologies (traumatic, ischemic, and hemorrhagic) and lesion locations across the cervical, thoracic and lumbar spine. A deep learning model, SCIseg, was trained in a three-phase process involving active learning for the automatic segmentation of intramedullary SCI lesions and the spinal cord. The segmentations from the proposed model were visually and quantitatively compared with those from three other open-source methods (PropSeg, DeepSeg and contrast-agnostic, all part of the Spinal Cord Toolbox). Wilcoxon signed-rank test was used to compare quantitative MRI biomarkers of SCI (lesion volume, lesion length, and maximal axial damage ratio) derived from the manual reference standard lesion masks and biomarkers obtained automatically with SCIseg segmentations. Results SCIseg achieved a Dice score of 0.92 ± 0.07 (mean ± SD) and 0.61 ± 0.27 for spinal cord and SCI lesion segmentation, respectively. There was no evidence of a difference between lesion length (P = .42) and maximal axial damage ratio (P = .16) computed from manually annotated lesions and the lesion segmentations obtained using SCIseg. Conclusion SCIseg accurately segmented intramedullary lesions on a diverse dataset of T2-weighted MRI scans and extracted relevant lesion biomarkers (namely, lesion volume, lesion length, and maximal axial damage ratio). SCIseg is open-source and accessible through the Spinal Cord Toolbox (v6.2 and above). Published under a CC BY 4.0 license.

Targeted-delivery of nanomedicine-enabled methylprednisolone to injured spinal cord promotes neuroprotection and functional recovery after acute spinal cord injury in rats

To date, no therapy has been proven to be efficacious in fully restoring neurological functions after spinal cord injury (SCI). Systemic high-dose methylprednisolone (MP) improves neurological recovery after acute SCI in both animal and human. MP therapy remains controversial due to its modest effect on functional recovery and significant adverse effects. To overcome the limitation of MP therapy, we have developed a N-(2-hydroxypropyl) methacrylamide copolymer-based MP prodrug nanomedicine (Nano-MP) that can selectively deliver MP to the SCI lesion when administered systemically in a rat model of acute SCI. Our in vivo data reveal that Nano-MP is significantly more effective than free MP in attenuating secondary injuries and neuronal apoptosis. Nano-MP is superior to free MP in improving functional recovery after acute SCI in rats. These data support Nano-MP as a promising neurotherapeutic candidate, which may provide potent neuroprotection and accelerate functional recovery with improved safety for patients with acute SCI.

Targeting foamy macrophages by manipulating ABCA1 expression to facilitate lesion healing in the injured spinal cord

Spinal cord injury (SCI) triggers a complex cascade of events, including myelin loss, neuronal damage, neuroinflammation, and the accumulation of damaged cells and debris at the injury site. Infiltrating bone marrow derived macrophages (BMDMϕ) migrate to the epicenter of the SCI lesion, where they engulf cell debris including abundant myelin debris to become pro-inflammatory foamy macrophages (foamy Mϕ), participate neuroinflammation, and facilitate the progression of SCI. This study aimed to elucidate the cellular and molecular mechanisms underlying the functional changes in foamy Mϕ and their potential implications for SCI. Contusion at T10 level of the spinal cord was induced using a New York University (NYU) impactor (5 g rod from a height of 6.25 mm) in male mice. ABCA1, an ATP-binding cassette transporter expressed by Mϕ, plays a crucial role in lipid efflux from foamy cells. We observed that foamy Mϕ lacking ABCA1 exhibited increased lipid accumulation and a higher presence of lipid-accumulated foamy Mϕ as well as elevated pro-inflammatory response in vitro and in injured spinal cord. We also found that both genetic and pharmacological enhancement of ABCA1 expression accelerated lipid efflux from foamy Mϕ, reduced lipid accumulation and inhibited the pro-inflammatory response of foamy Mϕ, and accelerated clearance of cell debris and necrotic cells, which resulted in functional recovery. Our study highlights the importance of understanding the pathologic role of foamy Mϕ in SCI progression and the potential of ABCA1 as a therapeutic target for modulating the inflammatory response, promoting lipid metabolism, and facilitating functional recovery in SCI.

An individual participant meta-analysis of mirabegron in multiple sclerosis and spinal cord injury.

Our objective was to conduct an individual patient data meta-analysis (IPDMA) of the two published randomized placebo-controlled trials of mirabegron in people with neurogenic lower urinary tract dysfunction (NLUTD) due to spinal cord injury (SCI) or multiple sclerosis (MS). We identified two randomized, placebo-controlled trials. We extracted individual patient data from the trials and evaluated two primary outcomes: change in maximum cystometric capacity and change in the patient perception of bladder condition (PPBC). We also evaluated several secondary outcomes related to urodynamic function and quality of life. We conducted three exploratory analyses to test hypotheses based on our clinical experiences with mirabegron in NLUTD. Analysis of covariance with adjustment for baseline values was used for the statistical analysis. Our IPDMA included 98 patients from the two trials. The results showed that mirabegron was associated with a significant improvement in maximum cystometric capacity (+41 mL, p = 0.04) and in the PPBC (-0.8, p < 0.01) compared to placebo. Secondary outcomes including peak neurogenic detrusor overactivity pressure (-20 cm H2O, p < 0.01), incontinence-QOL score (+12, p < 0.01), and 24 h pad weights (-79 g, p = 0.04) also improved significantly compared to placebo. Exploratory analyses found similar improvements in people with MS and SCI; some outcomes improved to a greater degree among people with incomplete SCI,or SCIs that were below T7. Our IPDMA provides evidence supporting the use of mirabegron in patients with NLUTD due to SCI or MS. Further work evaluating differential responses in people with different SCI lesion characteristics may be warranted.

Enzyme-immobilized nanoclay hydrogel simultaneously reduces inflammation and scar deposition to treat spinal cord injury

Spinal cord injury (SCI) is a severely disabling pathological condition and always results in sensory and motor functions loss. After SCI, inflammation-mediated secondary tissue damage and subsequent formation of neuroglial scar suppress neuron survival and regeneration, therefore resulting in severe neurofunctional dysfunction. Although nanoclay biomaterials demonstrated useful immunomodulation feature in non-neuronal tissue, it is unclear if they can inhibit inflammation in SCI lesions and promote neurofunctional recovery. In this study, we immobilized chondroitinase ABC enzyme (ChABC), which can degrade chondroitin sulfate proteoglycans (CSPGs) of neuroglial scar, inside nanoclay (Laponite®, Lap) hydrogel through electrostatic interaction. The presented ChABC-immobilized Lap hydrogel (ChABC@Lap) exhibited shear-thinning properties and excellent injectability, allowing to locally deliver it into injured area through a non-invasive manner. Cell biological experiments and SCI rat model research revealed that both pure Lap (without ChABC) and ChABC@Lap hydrogels significantly reduced pro-inflammatory macrophage marker (iNOS) intensity. Importantly, compared with Lap hydrogel, ChABC@Lap hydrogel significantly decreased GFAP and CS-56 marked scar deposition, increased Tuj-1+ neurons regeneration, and promoted NF200+ neurons survival, thereby improving SCI rat of electrophysiological characteristics and motor function. In summary, the designed enzyme-immobilized nanoclay hydrogel offers a promising strategy for SCI therapy through modulating simultaneously inflammation and glial scar deposition.

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. Moreover, 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 particularly 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.

HGFIN deficiency exacerbates spinal cord injury by promoting inflammation and cell apoptosis through regulation of the PI3K/AKT signaling pathway.

Spinal cord injury (SCI) is a devastating neurological disease characterized by neuroinflammation and neuronal apoptosis. The PI3K/AKT signaling pathway is related to the pathological process of SCI. Hematopoietic growth factor inducible neurokinin-1 type (HGFIN) is a transmembrane glycoprotein that exerts neuroprotective actions in various neurodegenerative diseases. However, the potential role and mechanism of HGFIN in the development of SCI are still unclear. To investigate the effect of HGFIN on inflammation and neuronal apoptosis as well as the underlying mechanism in SCI. A rat model of SCI was established, and Basso-Beattie-Bresnahan (BBB) motor function assay was performed to detect motor function. Expression of HGFIN was measured at 7 days after injury by western blot and immunofluorescence. An HGFIN-shRNA-carrying lentivirus was injected into the injury site to block the expression of HGFIN. The effects of HGFIN on neuronal apoptosis and the PI3K/AKT pathway were analyzed by TUNEL staining and immunofluorescence. The Iba-1 expression and the levels of pro-inflammatory cytokines were measured in spinal cord tissues by immunofluorescence staining and real-time polymerase chain reaction (PCR) analysis. The SCI rats showed increased expression of HGFIN in spinal cord tissues. The HGFIN deficiency aggravated SCI lesions, as evidenced by decreased BBB scores. At 7 days post-injury, HGFIN knockdown promoted neuronal apoptosis, accompanied by the increased expression level of the apoptosis effector cleaved caspase-3 and cleaved PARP, and decreased anti-apoptotic protein Bcl-2 expression. Moreover, HGFIN knockdown aggravated the inflammation process, indicated by increased Iba1-positive cells. The HGFIN knockdown increased the production of pro-inflammatory cytokines including IL-1β, TNF-α and IL-6. Further analysis revealed that HGFIN deficiency reduced the activation of the PI3K/AKT pathway in spinal cord tissue after injury. Lentivirus-mediated downregulation of HGFIN exacerbates inflammation and neuronal apoptosis in SCI by regulating the PI3K/AKT pathway, and provides clues for developing novel therapeutic approaches and targets against SCI.

Hydrogel and Nanomedicine-Based Multimodal Therapeutic Strategies for Spinal Cord Injury.

Spinal cord injury (SCI) is a severe neurodegenerative disease caused by mechanical and biological factors, manifesting as a loss of motor and sensory functions. Inhibition of injury expansion and even reversal of injury in the acute damage stage of SCI are important strategies for treating this disease. Hydrogels and nanoparticle (NP)-based drugs are the most effective, widely studied, and clinically valuable therapeutic strategies in the field of repair and regeneration. Hydrogels are 3D flow structures that fill the pathological gaps in SCI and provide a microenvironment similar to that of the spinal cord extracellular matrix for nerve cell regeneration. NP-based drugs can easily penetrate the blood-spinal cord barrier, target SCI lesions, and are noninvasive. Hydrogels and NPs as drug carriers can be loaded with various drugs and biological therapeutic factors for slow release in SCI lesions. They help drugs function more efficiently by exerting anti-inflammatory, antioxidant, and nerve regeneration effects to promote the recovery of neurological function. In this review, the use of hydrogels and NPs as drug carriers and the role of both in the repair of SCI are discussed to provide a multimodal strategic reference for nerve repair and regeneration after SCI.

Post Doc Competition (Knowledge Generation) ID 1986617

Background Transcutaneous spinal stimulation (TSS) is emerging as a valuable tool for electrophysiological and clinical assessments. Objective The objectives of this study were to investigate: (1) TSS above and below a spinal cord injury (SCI) lesion results in different recruitment pattern of upper limb (UL) motor pools compared to neurologically intact subjects (NIS), and (2) the relationship between recruitment pattern of UL motor pools and neurological and functional status in individuals with SCI. Methods: Eleven NIS and six participants with cervical SCI were recruited in this study. We compared spinally evoked motor potentials in UL muscles during TSS delivered to the cervical spinal cord between the spinous process of C3-C4 and C7-T1 vertebrae. Results As expected, TSS delivered over the cervical spinal cord in NIS can preferentially activate proximal and distal muscles along the rostrocaudal axis, as well as ipsilateral UL muscles along the mediolateral axis. However, in participants with SCI, the responses registered in UL muscles innervated by motor pools above and below the lesion demonstrated different recruitment compared to NIS, and were dependent on the level, extent, and side of SCI. Conclusions The spatial map obtained from assessing evoked potentials above and below the lesion contributes to the comprehensive understanding of the viability and function of specific UL motor pools, and can be utilized to monitor changes in recruitment patterns of the UL motor pools during neurorehabilitation interventions after SCI.

Application of Conductive Hydrogels on Spinal Cord Injury Repair: A Review.

Spinal cord injury (SCI) causes severe motor or sensory damage that leads to long-term disabilities due to disruption of electrical conduction in neuronal pathways. Despite current clinical therapies being used to limit the propagation of cell or tissue damage, the need for neuroregenerative therapies remains. Conductive hydrogels have been considered a promising neuroregenerative therapy due to their ability to provide a pro-regenerative microenvironment and flexible structure, which conforms to a complex SCI lesion. Furthermore, their conductivity can be utilized for noninvasive electrical signaling in dictating neuronal cell behavior. However, the ability of hydrogels to guide directional axon growth to reach the distal end for complete nerve reconnection remains a critical challenge. In this Review, we highlight recent advances in conductive hydrogels, including the incorporation of conductive materials, fabrication techniques, and cross-linking interactions. We also discuss important characteristics for designing conductive hydrogels for directional growth and regenerative therapy. We propose insights into electrical conductivity properties in a hydrogel that could be implemented as guidance for directional cell growth for SCI applications. Specifically, we highlight the practical implications of recent findings in the field, including the potential for conductive hydrogels to be used in clinical applications. We conclude that conductive hydrogels are a promising neuroregenerative therapy for SCI and that further research is needed to optimize their design and application.

Microneurotrophin BNN27 Reduces Astrogliosis and Increases Density of Neurons and Implanted Neural Stem Cell-Derived Cells after Spinal Cord Injury

Microneurotrophins, small-molecule mimetics of endogenous neurotrophins, have demonstrated significant therapeutic effects on various animal models of neurological diseases. Nevertheless, their effects on central nervous system injuries remain unknown. Herein, we evaluate the effects of microneurotrophin BNN27, an NGF analog, in the mouse dorsal column crush spinal cord injury (SCI) model. BNN27 was delivered systemically either by itself or combined with neural stem cell (NSC)-seeded collagen-based scaffold grafts, demonstrated recently to improve locomotion performance in the same SCI model. Data validate the ability of NSC-seeded grafts to enhance locomotion recovery, neuronal cell integration with surrounding tissues, axonal elongation and angiogenesis. Our findings also show that systemic administration of BNN27 significantly reduced astrogliosis and increased neuron density in mice SCI lesion sites at 12 weeks post injury. Furthermore, when BNN27 administration was combined with NSC-seeded PCS grafts, BNN27 increased the density of survived implanted NSC-derived cells, possibly addressing a major challenge of NSC-based SCI treatments. In conclusion, this study provides evidence that small-molecule mimetics of endogenous neurotrophins can contribute to effective combinatorial treatments for SCI, by simultaneously regulating key events of SCI and supporting grafted cell therapies in the lesion site.

Inflammatory stimulation of astrocytes affects the expression of miRNA-22-3p within NSCs-EVs regulating remyelination by targeting KDM3A

BackgroundEndogenous neural stem cells (NSCs) are critical for the remyelination of axons following spinal cord injury (SCI). Cell–cell communication plays a key role in the regulation of the differentiation of NSCs. Astrocytes act as immune cells that encounter early inflammation, forming a glial barrier to prevent the spread of destructive inflammation following SCI. In addition, the cytokines released from astrocytes participate in the regulation of the differentiation of NSCs. The aim of this study was to investigate the effects of cytokines released from inflammation-stimulated astrocytes on the differentiation of NSCs following SCI and to explore the influence of these cytokines on NSC–NSC communication.ResultsLipopolysaccharide stimulation of astrocytes increased bone morphogenetic protein 2 (BMP2) release, which not only promoted the differentiation of NSCs into astrocytes and inhibited axon remyelination in SCI lesions but also enriched miRNA-22-3p within extracellular vesicles derived from NSCs. These miRNA-22 molecules function as a feedback loop to promote NSC differentiation into oligodendrocytes and the remyelination of axons following SCI by targeting KDM3A.ConclusionsThis study revealed that by releasing BMP2, astrocytes were able to regulate the differentiation of NSCs and NSC–NSC communication by enriching miRNA-22 within NSC-EVs, which in turn promoted the regeneration and remyelination of axons by targeting the KDM3A/TGF-beta axis and the recovery of neurological outcomes following SCI.

Systematic Review of the Effectiveness of Using iPSC in Spinal Cord Injury

Damage to the spinal cord is the pathological condition known as spinal cord injury (SCI) or spinal cord injury. This ailment, which not only causes neurological impairments but also places a significant psychological and social burden on patients, has grown to be one of the most challenging worldwide health issues. A successful stem cell-based treatment has just been created and could be the answer to this medical issue. It has been demonstrated that iPSC-dNSC stem cells are efficient at both reducing post-traumatic inflammatory conditions and kicking off neuronal cell regeneration at the location of SCI lesions. The aim of this study to investigate the the effectiveness of using iPSC in spinal cord injury. This study used the literature review method by discovering articles using the search engine Google Scholar, and PubMed. According to the search results, 413 articles were obtained in accordance with the title of the study, but 8 articles met the inclusion criteria in this study. The findings of this study showed that the iPSC methodology was applied, as well as the advantages and results of the procedure. Using iPSCs to treat SCI is still challenging and needs additional investigation.

Lesion Extension and Neuronal Loss after Spinal Cord Injury Using X-Ray Phase-Contrast Tomography in Mice.

Following spinal cord injury (SCI) the degree of functional (motor, autonomous, or sensory) loss correlates with the severity of nervous tissue damage. An imaging technique able to capture non-invasively and simultaneously the complex mechanisms of neuronal loss, vascular damage, and peri-lesional tissue reorganization is currently lacking in experimental SCI studies. Synchrotron X-ray phase-contrast tomography (SXPCT) has emerged as a non-destructive three-dimensional (3D) neuroimaging technique with high contrast and spatial resolution. In this framework, we developed a multi-modal approach combining SXPCT, histology and correlative methods to study neurovascular architecture in normal and spinal level C4-contused mouse spinal cords (C57BL/6J mice, age 2-3 months). The evolution of SCI lesion was imaged at the cell resolution level during the acute (30 min) and subacute (7 day) phases. Spared motor neurons (MNs) were segmented and quantified in different volumes localized at and away from the epicenter. SXPCT was able to capture neuronal loss and blood-brain barrier breakdown following SCI. Three-dimensional quantification based on SXPCT acquisitions showed no additional MN loss between 30 min and 7 days post-SCI. In addition, the analysis of hemorrhagic (at 30 min) and lesion (at 7 days) volumes revealed a high similarity in size, suggesting no extension of tissue degeneration between early and later time-points. Moreover, glial scar borders were unevenly distributed, with rostral edges being the most extended. In conclusion, SXPCT capability to image at high resolution cellular changes in 3D enables the understanding of the relationship between hemorrhagic events and nervous structure damage in SCI.

Electroconductive PEDOT nanoparticle integrated scaffolds for spinal cord tissue repair

BackgroundHostile environment around the lesion site following spinal cord injury (SCI) prevents the re-establishment of neuronal tracks, thus significantly limiting the regenerative capability. Electroconductive scaffolds are emerging as a promising option for SCI repair, though currently available conductive polymers such as polymer poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) present poor biofunctionality and biocompatibility, thus limiting their effective use in SCI tissue engineering (TE) treatment strategies.MethodsPEDOT NPs were synthesized via chemical oxidation polymerization in miniemulsion. The conductive PEDOT NPs were incorporated with gelatin and hyaluronic acid (HA) to create gel:HA:PEDOT-NPs scaffolds. Morphological analysis of both PEDOT NPs and scaffolds was conducted via SEM. Further characterisation included dielectric constant and permittivity variances mapped against morphological changes after crosslinking, Young’s modulus, FTIR, DLS, swelling studies, rheology, in-vitro, and in-vivo biocompatibility studies were also conducted.ResultsIncorporation of PEDOT NPs increased the conductivity of scaffolds to 8.3 × 10–4 ± 8.1 × 10–5 S/cm. The compressive modulus of the scaffold was tailored to match the native spinal cord at 1.2 ± 0.2 MPa, along with controlled porosity. Rheological studies of the hydrogel showed excellent 3D shear-thinning printing capabilities and shape fidelity post-printing. In-vitro studies showed the scaffolds are cytocompatible and an in-vivo assessment in a rat SCI lesion model shows glial fibrillary acidic protein (GFAP) upregulation not directly in contact with the lesion/implantation site, with diminished astrocyte reactivity. Decreased levels of macrophage and microglia reactivity at the implant site is also observed. This positively influences the re-establishment of signals and initiation of healing mechanisms. Observation of axon migration towards the scaffold can be attributed to immunomodulatory properties of HA in the scaffold caused by a controlled inflammatory response. HA limits astrocyte activation through its CD44 receptors and therefore limits scar formation. This allows for a superior axonal migration and growth towards the targeted implantation site through the provision of a stimulating microenvironment for regeneration.ConclusionsBased on these results, the incorporation of PEDOT NPs into Gel:HA biomaterial scaffolds enhances not only the conductive capabilities of the material, but also the provision of a healing environment around lesions in SCI. Hence, gel:HA:PEDOT-NPs scaffolds are a promising TE option for stimulating regeneration for SCI.

Clinical Venous Thromboembolism in Spinal Trauma with and Without Spinal Cord Injury: A 3-Year Experience of Midlands Centre for Spinal Injuries, Oswestry, UK

Background and Aims: This study aimed to determine the incidence of deep-vein thrombosis (DVT) and pulmonary embolism (PE) among patients admitted acutely to a regional spinal injury center, following spinal trauma; to compare its occurrence between those with spinal cord injury (SCI) and those without; and to assess the effect of various factors such as age, gender, neurological impairment, and duration of prophylaxis on the incidence observed. Patients and Methods: We retrospectively reviewed the charts of 374 consecutive patients who sustained traumatic spinal injury and were admitted acutely to the Midlands Centre for Spinal Injuries, Oswestry (UK), over a 3-year period. A total of 159 patients had spinal trauma with SCI and 215 were neurologically intact. The majority of these patients were treated nonsurgically and received the same thromboprophylactic regimen started within a median of 2 days postinjury. The incidence of clinical VTE (DVT and PE) was determined and some risk factors were assessed. Ethical approval was obtained through the Audit Office Committee of the Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry. Results: Among the neurologically intact group, one patient developed clinical PE (0.5%). Out of 159 patients with SCI, 23 developed clinically evident VTE (14.5%), 15 had DVT (11.9%), 4 had PE (5%), and 4 had both DVT and PE. There was no fatality. Complete SCI lesions were associated with higher incidence of VTE compared to incomplete lesions, 17.6% and 11%, respectively (P &lt; 0.001). There were two peaks of thromboembolic episodes: the first during the first 2 weeks after injury (30% of cases) and the second was after the 8th week postinjury (38% of cases). A higher incidence of VTE was recorded in males than females (14.3% and 7.9%, respectively). Aso, the incidence of VTE is slightly higher in the age group between 40 and 60 years, but these differences were not statistically significant. Conclusions: SCI is associated with high risk of venous thromboembolism, and the risk increases with the severity of cord insult. While spinal column injury is shown to be associated with much lower risk. The risk is reduced with strict adherence to thromboprophylactic regimen which we suggest to continue for at least 12 weeks for SCI patients.

Magnesium Oxide/Poly(l-lactide-co-ε-caprolactone) Scaffolds Loaded with Neural Morphogens Promote Spinal Cord Repair through Targeting the Calcium Influx and Neuronal Differentiation of Neural Stem Cells.

Because of the limited regenerative ability of the central nervous system (CNS), effective treatments for spinal cord injury (SCI) are still lacking. After SCI, neuron loss and axon regeneration failure often result in irreversible functional impairment. The calcium overload induced by the N-methyl-D-aspartate receptor (NMDAR) overactivation is critical for cell death in SCI. It has been reported that the magnesium ion (Mg2+ ) can competitively block the NMDAR and reduce the calcium influx, and that sonic hedgehog (Shh) and retinoic acid (RA) are the critical regulators of neuronal differentiation of endogenous neural stem cells (NSCs). Here, magnesium oxide (MgO)/poly (l-lactide-co-ε-caprolactone) (PLCL) scaffold loaded with purmorphamine (PUR, a Shh signaling agonist) and RA is developed and its feasibility in SCI repair is tested. The results showed that the Mg2+ released from MgO attenuated cell apoptosis by blocking the calcium influx, and the PUR/RA promoted the recruitment and neuronal differentiation of endogenous NSCs, thereby reducing the glial scar formation at the SCI lesion site. Furthermore, implantation of PUR/RA-loaded MgO/PLCL scaffold facilitates the partial recovery of a locomotor function of SCI mouse in vivo. Together, findings from this study imply that PUR/RA-loaded MgO/PLCL scaffold may be a promising biomaterial for the clinical treatment of SCI.

Neurogenic bladder in patients with paraplegia: a two-center study of the real-life experience of the patients' journey.

Several patterns of urological dysfunctions have been described following spinal cord injury (SCI), depending on the level and the completeness of the injury. A better understanding of the natural history of neurogenic bladder in patients with SCI, and the description of their successive therapeutic lines based on their clinical and urodynamic pattern is needed to improve their management. This study aimed to describe the real-life successive therapeutic lines in patients with neurogenic lower urinary tract dysfunction (NLUTD) following SCI. We conducted a two-center retrospective review of medical files of patients with SCI followed in two French specialized departments of Physical Medicine and Rehabilitation between January 2000 and January 2018. All patients with SCI with a level of lesion bellow T3 and older than 18years old were eligible. The primary outcome was the description of the natural journey of neurogenic bladder in this population, from the awakening bladder contraction to the last therapeutic line. Survival curves were calculated with a 95-confidence interval using the Kaplan-Meier method. One hundred and five patients were included in this study. Most of the patients were young men with a complete SCI lesion. The median time of treatment introduction was 1 and 9years for anticholinergics and intradetrusor injection of BoNT/A, respectively. Median duration of effect of treatments was 4 and 6years post-introduction of anticholinergics and BoNT/A, respectively. This study describes NLUTD journey of patients with SCI demonstrating the mid-term efficacy of the two first therapeutic lines of NDO management. An improvement of non-surgical therapeutics is needed.

Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis

Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis