Advancements in the Treatment of Spinal Cord Injury

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 27740

Special Issue Editor

1. Institute of Experimental Medicine, Czech Academy of Sciences, Vídeňská 1083, Prague, Czech Republic
2. Department of Neurosurgery, Charles University, Medical Faculty and University Hospital Hradec Králové, Sokolska 581, Hradec Kralove, Czech Republic
Interests: spinal cord injury; neuroinflammation; electrical epidural stimulation; glioblastoma therapy; liquid biopsy; circulating tumor cells

Special Issue Information

Dear Colleagues,

Traumatic spinal cord injury (SCI) often results in severe disability and remains a major challenging medical condition. Various levels of loss of motor and sensory functions below the injury are a result of pathophysiological cascades known as secondary injury, which follows direct (primary) injury. Regeneration of the neural tissue is limited by expression of multiple inhibitory factors as well as mechanical barriers including glial scarring or cystic cavitations. Multiple studies have reported promising results by various mechanisms. Alleviating the harmful effect of the secondary injury can be achieved through growth factors, anti-inflammatory therapy, enzymatic therapy, etc. Regeneration of the endogenous neurons is supported by cell therapy facilitated by biomaterial implantation, usually with bioactive components. Intensive rehabilitation and neuromodulation is focused mainly on maximal utilization of the residual functional tissue. The united aim of the treatment is to functionally rewire supralesional and sublesional spinal cord, enabling volitional motor control of previously paralyzed functions. It has also been previously shown that a combination of various strategies potentiates the beneficial effect of the treatment. Despite extensive research in the field, though, the ideal combination of a therapeutic approach is still not known. We cordially invite you to contribute to the Special Issue entitled “Advancements in the Treatment of Spinal Cord Injury” focused on cutting-edge research of SCI. Our aim is to provide most relevant information on innovative treatment modalities and their combinations and updates in understanding of pathophysiological processes followed by reorganization of the spinal cord. Original investigations and review articles are both welcome.

Dr. Petr Krupa
Guest Editor

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Keywords

  • spinal cord injury
  • neuromodulation
  • rehabilitation
  • neuroplasticity
  • neuroregeneration
  • cell therapy growth factors
  • astrogliosis
  • neuroinflammation

Published Papers (8 papers)

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Research

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20 pages, 3761 KiB  
Article
L-Arginine Depletion Improves Spinal Cord Injury via Immunomodulation and Nitric Oxide Reduction
by Céline Erens, Jana Van Broeckhoven, Cindy Hoeks, Gernot Schabbauer, Paul N. Cheng, Li Chen, Niels Hellings, Bieke Broux, Stefanie Lemmens and Sven Hendrix
Biomedicines 2022, 10(2), 205; https://doi.org/10.3390/biomedicines10020205 - 18 Jan 2022
Cited by 10 | Viewed by 2850
Abstract
Background: Spinal cord injury (SCI) elicits robust neuroinflammation that eventually exacerbates the initial damage to the spinal cord. L-arginine is critical for the responsiveness of T cells, which are important contributors to neuroinflammation after SCI. Furthermore, L-arginine is the substrate for nitric oxide [...] Read more.
Background: Spinal cord injury (SCI) elicits robust neuroinflammation that eventually exacerbates the initial damage to the spinal cord. L-arginine is critical for the responsiveness of T cells, which are important contributors to neuroinflammation after SCI. Furthermore, L-arginine is the substrate for nitric oxide (NO) production, which is a known inducer of secondary damage. Methods: To accomplish systemic L-arginine depletion, repetitive injections of recombinant arginase-1 (rArg-I) were performed. Functional recovery and histopathological parameters were analyzed. Splenic immune responses were evaluated by flow cytometry. Pro-inflammatory gene expression and nitrite concentrations were measured. Results: We show for the first time that systemic L-arginine depletion improves locomotor recovery. Flow cytometry and immunohistological analysis showed that intraspinal T-cell infiltration was reduced by 65%, and peripheral numbers of Th1 and Th17 cells were suppressed. Moreover, rArg-I treatment reduced the intraspinal NO production by 40%. Histopathological analyses revealed a 37% and 36% decrease in the number of apoptotic neurons and neuron-macrophage/microglia contacts in the spinal cord, respectively. Conclusions: Targeting detrimental T-cell responses and NO-production via rArg-I led to a reduced neuronal cell death and an improved functional recovery. These findings indicate that L-arginine depletion holds promise as a therapeutic strategy after SCI. Full article
(This article belongs to the Special Issue Advancements in the Treatment of Spinal Cord Injury)
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19 pages, 9793 KiB  
Article
A Hyaluronic Acid Demilune Scaffold and Polypyrrole-Coated Fibers Carrying Embedded Human Neural Precursor Cells and Curcumin for Surface Capping of Spinal Cord Injuries
by Hoda Elkhenany, Pablo Bonilla, Esther Giraldo, Ana Alastrue Agudo, Michael J. Edel, María Jesus Vicent, Fernando Gisbert Roca, Cristina Martínez Ramos, Laura Rodríguez Doblado, Manuel Monleón Pradas and Victoria Moreno Manzano
Biomedicines 2021, 9(12), 1928; https://doi.org/10.3390/biomedicines9121928 - 16 Dec 2021
Cited by 17 | Viewed by 4385
Abstract
Tissue engineering, including cell transplantation and the application of biomaterials and bioactive molecules, represents a promising approach for regeneration following spinal cord injury (SCI). We designed a combinatorial tissue-engineered approach for the minimally invasive treatment of SCI—a hyaluronic acid (HA)-based scaffold containing polypyrrole-coated [...] Read more.
Tissue engineering, including cell transplantation and the application of biomaterials and bioactive molecules, represents a promising approach for regeneration following spinal cord injury (SCI). We designed a combinatorial tissue-engineered approach for the minimally invasive treatment of SCI—a hyaluronic acid (HA)-based scaffold containing polypyrrole-coated fibers (PPY) combined with the RAD16-I self-assembling peptide hydrogel (Corning® PuraMatrix™ peptide hydrogel (PM)), human induced neural progenitor cells (iNPCs), and a nanoconjugated form of curcumin (CURC). In vitro cultures demonstrated that PM preserves iNPC viability and the addition of CURC reduces apoptosis and enhances the outgrowth of Nestin-positive neurites from iNPCs, compared to non-embedded iNPCs. The treatment of spinal cord organotypic cultures also demonstrated that CURC enhances cell migration and prompts a neuron-like morphology of embedded iNPCs implanted over the tissue slices. Following sub-acute SCI by traumatic contusion in rats, the implantation of PM-embedded iNPCs and CURC with PPY fibers supported a significant increase in neuro-preservation (as measured by greater βIII-tubulin staining of neuronal fibers) and decrease in the injured area (as measured by the lack of GFAP staining). This combination therapy also restricted platelet-derived growth factor expression, indicating a reduction in fibrotic pericyte invasion. Overall, these findings support PM-embedded iNPCs with CURC placed within an HA demilune scaffold containing PPY fibers as a minimally invasive combination-based alternative to cell transplantation alone. Full article
(This article belongs to the Special Issue Advancements in the Treatment of Spinal Cord Injury)
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17 pages, 5576 KiB  
Article
Repetitive Trans Spinal Magnetic Stimulation Improves Functional Recovery and Tissue Repair in Contusive and Penetrating Spinal Cord Injury Models in Rats
by Amandine Robac, Pauline Neveu, Alizée Hugede, Elisabeth Garrido, Lionel Nicol, Quentin Delarue and Nicolas Guérout
Biomedicines 2021, 9(12), 1827; https://doi.org/10.3390/biomedicines9121827 - 3 Dec 2021
Cited by 8 | Viewed by 1997
Abstract
Spinal cord injury (SCI) is an incurable condition in which the brain is disconnected partially or completely from the periphery. Mainly, SCIs are traumatic and are due to traffic, domestic or sport accidents. To date, SCIs are incurable and, most of the time, [...] Read more.
Spinal cord injury (SCI) is an incurable condition in which the brain is disconnected partially or completely from the periphery. Mainly, SCIs are traumatic and are due to traffic, domestic or sport accidents. To date, SCIs are incurable and, most of the time, leave the patients with a permanent loss of sensitive and motor functions. Therefore, for several decades, researchers have tried to develop treatments to cure SCI. Among them, recently, our lab has demonstrated that, in mice, repetitive trans-spinal magnetic stimulation (rTSMS) can, after SCI, modulate the lesion scar and can induce functional locomotor recovery non-invasively. These results are promising; however, before we can translate them to humans, it is important to reproduce them in a more clinically relevant model. Indeed, SCIs do not lead to the same cellular events in mice and humans. In particular, SCIs in humans induce the formation of cystic cavities. That is why we propose here to validate the effects of rTSMS in a rat animal model in which SCI leads to the formation of cystic cavities after penetrating and contusive SCI. To do so, several techniques, including immunohistochemical, behavioral and MRI, were performed. Our results demonstrate that rTSMS, in both SCI models, modulates the lesion scar by decreasing the formation of cystic cavities and by improving axonal survival. Moreover, rTSMS, in both models, enhances functional locomotor recovery. Altogether, our study describes that rTSMS exerts positive effects after SCI in rats. This study is a further step towards the use of this treatment in humans. Full article
(This article belongs to the Special Issue Advancements in the Treatment of Spinal Cord Injury)
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19 pages, 5049 KiB  
Article
Involvement of mTOR Pathways in Recovery from Spinal Cord Injury by Modulation of Autophagy and Immune Response
by Ingrid Vargova, Lucia Machova Urdzikova, Kristyna Karova, Barbora Smejkalova, Tolga Sursal, Veronika Cimermanova, Karolina Turnovcova, Chirag D. Gandhi, Meena Jhanwar-Uniyal and Pavla Jendelova
Biomedicines 2021, 9(6), 593; https://doi.org/10.3390/biomedicines9060593 - 24 May 2021
Cited by 10 | Viewed by 3548
Abstract
Traumatic spinal cord injury (SCI) is untreatable and remains the leading cause of disability. Neuroprotection and recovery after SCI can be partially achieved by rapamycin (RAPA) treatment, an inhibitor of mTORC1, complex 1 of the mammalian target of rapamycin (mTOR) pathway. However, mechanisms [...] Read more.
Traumatic spinal cord injury (SCI) is untreatable and remains the leading cause of disability. Neuroprotection and recovery after SCI can be partially achieved by rapamycin (RAPA) treatment, an inhibitor of mTORC1, complex 1 of the mammalian target of rapamycin (mTOR) pathway. However, mechanisms regulated by the mTOR pathway are not only controlled by mTORC1, but also by a second mTOR complex (mTORC2). Second-generation inhibitor, pp242, inhibits both mTORC1 and mtORC2, which led us to explore its therapeutic potential after SCI and compare it to RAPA treatment. In a rat balloon-compression model of SCI, the effect of daily RAPA (5 mg/kg; IP) and pp242 (5 mg/kg; IP) treatment on inflammatory responses and autophagy was observed. We demonstrated inhibition of the mTOR pathway after SCI through analysis of p-S6, p-Akt, and p-4E-BP1 levels. Several proinflammatory cytokines were elevated in pp242-treated rats, while RAPA treatment led to a decrease in proinflammatory cytokines. Both RAPA and pp242 treatments caused an upregulation of LC3B and led to improved functional and structural recovery in acute SCI compared to the controls, however, a greater axonal sprouting was seen following RAPA treatment. These results suggest that dual mTOR inhibition by pp242 after SCI induces distinct mechanisms and leads to recovery somewhat inferior to that following RAPA treatment. Full article
(This article belongs to the Special Issue Advancements in the Treatment of Spinal Cord Injury)
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14 pages, 33471 KiB  
Article
Promoting Neuronal Outgrowth Using Ridged Scaffolds Coated with Extracellular Matrix Proteins
by Ahad M. Siddiqui, Rosa Brunner, Gregory M. Harris, Alan Lee Miller II, Brian E. Waletzki, Ann M. Schmeichel, Jean E. Schwarzbauer, Jeffrey Schwartz, Michael J. Yaszemski, Anthony J. Windebank and Nicolas N. Madigan
Biomedicines 2021, 9(5), 479; https://doi.org/10.3390/biomedicines9050479 - 27 Apr 2021
Cited by 11 | Viewed by 3007
Abstract
Spinal cord injury (SCI) results in cell death, demyelination, and axonal loss. The spinal cord has a limited ability to regenerate, and current clinical therapies for SCI are not effective in helping promote neurologic recovery. We have developed a novel scaffold biomaterial that [...] Read more.
Spinal cord injury (SCI) results in cell death, demyelination, and axonal loss. The spinal cord has a limited ability to regenerate, and current clinical therapies for SCI are not effective in helping promote neurologic recovery. We have developed a novel scaffold biomaterial that is fabricated from the biodegradable hydrogel oligo(poly(ethylene glycol)fumarate) (OPF). We have previously shown that positively charged OPF scaffolds (OPF+) in an open spaced, multichannel design can be loaded with Schwann cells to support axonal generation and functional recovery following SCI. We have now developed a hybrid OPF+ biomaterial that increases the surface area available for cell attachment and that contains an aligned microarchitecture and extracellular matrix (ECM) proteins to better support axonal regeneration. OPF+ was fabricated as 0.08 mm thick sheets containing 100 μm high polymer ridges that self-assemble into a spiral shape when hydrated. Laminin, fibronectin, or collagen I coating promoted neuron attachment and axonal outgrowth on the scaffold surface. In addition, the ridges aligned axons in a longitudinal bipolar orientation. Decreasing the space between the ridges increased the number of cells and neurites aligned in the direction of the ridge. Schwann cells seeded on laminin coated OPF+ sheets aligned along the ridges over a 6-day period and could myelinate dorsal root ganglion neurons over 4 weeks. This novel scaffold design, with closer spaced ridges and Schwann cells, is a novel biomaterial construct to promote regeneration after SCI. Full article
(This article belongs to the Special Issue Advancements in the Treatment of Spinal Cord Injury)
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18 pages, 7322 KiB  
Article
New Model of Ventral Spinal Cord Lesion Induced by Balloon Compression in Rats
by Petr Krupa, Katerina Stepankova, Jessica CF. Kwok, James W. Fawcett, Veronika Cimermanova, Pavla Jendelova and Lucia Machova Urdzikova
Biomedicines 2020, 8(11), 477; https://doi.org/10.3390/biomedicines8110477 - 5 Nov 2020
Cited by 3 | Viewed by 2637
Abstract
Despite the variety of experimental models of spinal cord injury (SCI) currently used, the model of the ventral compression cord injury, which is commonly seen in humans, is very limited. Ventral balloon compression injury reflects the common anatomical mechanism of a human lesion [...] Read more.
Despite the variety of experimental models of spinal cord injury (SCI) currently used, the model of the ventral compression cord injury, which is commonly seen in humans, is very limited. Ventral balloon compression injury reflects the common anatomical mechanism of a human lesion and has the advantage of grading the injury severity by controlling the inflated volume of the balloon. In this study, ventral compression of the SCI was performed by the anterior epidural placement of the balloon of a 2F Fogarty’s catheter, via laminectomy, at the level of T10. The balloon was rapidly inflated with 10 or 15 μL of saline and rested in situ for 5 min. The severity of the lesion was assessed by behavioral and immunohistochemical tests. Compression with the volume of 15 μL resulted in severe motor and sensory deficits represented by the complete inability to move across a horizontal ladder, a final Basso, Beattie and Bresnahan (BBB) score of 7.4 and a decreased withdrawal time in the plantar test (11.6 s). Histology and immunohistochemistry revealed a significant loss of white and gray matter with a loss of motoneuron, and an increased size of astrogliosis. An inflation volume of 10 μL resulted in a mild transient deficit. There are no other balloon compression models of ventral spinal cord injury. This study provided and validated a novel, easily replicable model of the ventral compression SCI, introduced by an inflated balloon of Fogarty´s catheter. For a severe incomplete deficit, an inflated volume should be maintained at 15 μL. Full article
(This article belongs to the Special Issue Advancements in the Treatment of Spinal Cord Injury)
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12 pages, 1971 KiB  
Communication
Neuroprotective Effect of Subdural Infusion of Serp-1 in Spinal Cord Trauma
by Jacek M. Kwiecien, Wojciech Dabrowski, Bryce J. Kwiecien-Delaney, Christian J. Kwiecien-Delaney, Dorota Siwicka-Gieroba, Jordan R. Yaron, Liqiang Zhang, Kathleen H. Delaney and Alexandra R. Lucas
Biomedicines 2020, 8(10), 372; https://doi.org/10.3390/biomedicines8100372 - 23 Sep 2020
Cited by 13 | Viewed by 2467
Abstract
Spinal cord injury (SCI) initiates a severe, destructive inflammation with pro-inflammatory, CD68+/CD163−, phagocytic macrophages infiltrating the area of necrosis and hemorrhage by day 3 and persisting for the next 16 weeks. Inhibition of macrophage infiltration of the site of necrosis that is converted [...] Read more.
Spinal cord injury (SCI) initiates a severe, destructive inflammation with pro-inflammatory, CD68+/CD163−, phagocytic macrophages infiltrating the area of necrosis and hemorrhage by day 3 and persisting for the next 16 weeks. Inhibition of macrophage infiltration of the site of necrosis that is converted into a cavity of injury (COI) during the first week post-SCI, should limit inflammatory damage, shorten its duration and result in neuroprotection. By sustained subdural infusion we administered Serp-1, a Myxoma virus-derived immunomodulatory protein previously shown to improve neurologic deficits and inhibit macrophage infiltration in the COI in rats with the balloon crush SCI. Firstly, in a 7 day long study, we determined that the optimal dose for macrophage inhibition was 0.2 mg/week. Then, we demonstrated that a continuous subdural infusion of Serp-1 for 8 weeks resulted in consistently accelerated lowering of pro-inflammatory macrophages in the COI and in their almost complete elimination similar to that previously observed at 16 weeks in untreated SCI rats. The macrophage count in the COI is a quantitative test directly related to the severity of destructive inflammation initiated by the SCI. This test has consistently demonstrated anti-inflammatory effect of Serp-1 interpreted as neuroprotection, the first and necessary step in a therapeutic strategy in neurotrauma. Full article
(This article belongs to the Special Issue Advancements in the Treatment of Spinal Cord Injury)
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Review

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25 pages, 4003 KiB  
Review
Planet of the AAVs: The Spinal Cord Injury Episode
by Katerina Stepankova, Pavla Jendelova and Lucia Machova Urdzikova
Biomedicines 2021, 9(6), 613; https://doi.org/10.3390/biomedicines9060613 - 28 May 2021
Cited by 9 | Viewed by 5529
Abstract
The spinal cord injury (SCI) is a medical and life-disrupting condition with devastating consequences for the physical, social, and professional welfare of patients, and there is no adequate treatment for it. At the same time, gene therapy has been studied as a promising [...] Read more.
The spinal cord injury (SCI) is a medical and life-disrupting condition with devastating consequences for the physical, social, and professional welfare of patients, and there is no adequate treatment for it. At the same time, gene therapy has been studied as a promising approach for the treatment of neurological and neurodegenerative disorders by delivering remedial genes to the central nervous system (CNS), of which the spinal cord is a part. For gene therapy, multiple vectors have been introduced, including integrating lentiviral vectors and non-integrating adeno-associated virus (AAV) vectors. AAV vectors are a promising system for transgene delivery into the CNS due to their safety profile as well as long-term gene expression. Gene therapy mediated by AAV vectors shows potential for treating SCI by delivering certain genetic information to specific cell types. This review has focused on a potential treatment of SCI by gene therapy using AAV vectors. Full article
(This article belongs to the Special Issue Advancements in the Treatment of Spinal Cord Injury)
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