Open access

Introductory Chapter: Clinical Approaches for Treating Paraplegia

Written By

Diego Incontri-Abraham and José Juan Antonio Ibarra Arias

Published: May 12th, 2021

DOI: 10.5772/intechopen.97395

From the Edited Volume


Edited by José Juan Antonio Ibarra Arias and Carlos Alberto Cuellar Ramos

Chapter metrics overview

313 Chapter Downloads

View Full Metrics

1. Introduction to spinal cord injury: epidemiology and biopsychosocial impact

Spinal cord injury (SCI), either traumatic or non-traumatic in origin, is a devastating condition that produces long-term effects that persist throughout life and are associated with severe disability and handicap. Reported traumatic SCI annual incidence rates ranges from 12.1 to 57.8 cases per million. Motor vehicle collisions, falls, violence, and sports represent the leading causes. In comparison to traumatic SCI, there is little literature on non-traumatic SCI epidemiology. The etiologies of this type of SCI include vertebral spondylosis (spinal stenosis), tumorous compression, vascular ischemia, congenital diseases and inflammatory conditions [1, 2].

Depending on the level of SCI, patients experience paraplegia or tetraplegia. Paraplegia is defined as the impairment of sensory and/or motor function in lower extremities. Patients with incomplete paraplegia generally have a good prognosis in regaining locomotor ability (around 76% of patients) within a year. Complete paraplegic patients experience limited recovery of lower limb function if their neurological level of injury (NLI) is above T9. An NLI below T9 is associated with 38% chance of regaining some lower extremity function and only 4% chance of recovery to an incomplete status. On the other hand, tetraplegia is defined as partial or total loss of sensory and/or motor function in all four limbs and has a worse prognosis than paraplegia [3].

Spinal cord injury is a leading cause of disability, particularly in young adults. The highest incidences of SCI occur in persons between 20 and 40 years of age [4], being more common in males (82.8%) than females [5]. However, recent reports indicate an increase in SCI prevalence among older people and females. On the other hand, when classifying the types of disabilities caused by SCI, tetraplegia represents around 60%, while paraplegia represents approximately 40% [6]. Among all secondary complications following SCI, pressure ulcers, neurogenic bladder, urinary tract infections, pain, autonomic dysreflexia, osteoporosis, and muscle atrophy represent the majority. Currently, SCI complications management is challenging, and the outcomes are unsatisfactory [5, 7, 8, 9, 10]. Moreover, having SCI may increase the risk of developing a health condition that is an indirect consequence of the impairment itself, such as increasing sedentary behaviors that contribute to the development of obesity and diabetes. Psychological factors (depression, anxiety, drug and substance dependency, post-traumatic stress disorders, etc.) may also complicate these chronic health conditions [11]. In addition, SCI leads to an abrupt change in the professional life and future plans of the patients [12] due to the irreversible restriction of functional movement, affecting not only quality of life but also the ability to live independently. Furthermore, not only economic, educational and social conditions can affect SCI patients. Sexual relationships as well as marriage may be affected in patients who develop a severe disability following SCI [13, 14, 15]. These issues have been the most important motivation for the implementation of studies over the last decades that look for novel strategies for SCI. Despite all the progress in both preclinical and clinical studies, new therapies are still needed in order to improve both functional recovery and quality of life following SCI.

Lastly, it is important to mention that disparities between the developing and developed countries capacity to deliver emergency and acute care are evident immediately after a SCI. In many low-resource regions, these disparities can lead to further neurological compromise and poorer first year survival [16]. On the other hand, developed countries have significantly improved survival compared with developing countries. For example, tetraplegics have lower survival rates than paraplegics; however, in developed countries, this gap has narrowed considerably over the last 40 years. Developing countries still have the highest 1-year mortality rates [17].


2. The current understanding of the SCI pathophysiology and management

The immediate event arising from the primary injury consists in a mechanical disruption of tissue. Vascular changes, edema, hemorrhage, inflammation, neuronal, and myelin changes represent the acute phase (hours to 1–2 days). The edema may be vasogenic, defined as a breakdown of the blood–brain barrier (BBB) leading to the leakage of plasma fluid into the extracellular space. This may result in pressure-induced ischemia caused by reduced blood flow to the site of injury. Cytotoxic edema (intracellular swelling) also occur, particularly in astrocytes. Such edema is caused by pro-inflammatory factors, excitotoxicity, oxidative stress, lipid peroxidation, electrolyte imbalances, among others. In regard to neurons, the mode of death appears to be necrosis; however, neuronal apoptosis has been reported as well but only in experimental animals. Myelin breakdown occurs early following SCI and is characterized initially by swelling and ultimately by its fragmentation. During the intermediate phase (days to weeks), there will be several glial responses, necrotic debris will be eliminated, edema will resolve, and there will be revascularization of the tissue associated with a restoration of the BBB. Finally, the late phase of the SCI (weeks to months/years) is characterized by Wallerian degeneration, astroglial scar formation, development of cysts and syrinx, and schwannosis (aberrant intra- and extramedullary proliferation of Schwann cells with associated axons). The Wallerian degeneration is a process that consists in the anterograde disintegration of axons and their myelin sheaths that have been transected following injury. Eventually, an astroglial scar replaces the destroyed myelinated axons; however, this astroglial scar represents an impediment to regeneration [18].

SCI can be categorized also into primary and secondary phases. The primary SCI phase involves the initial mechanical injury (compression, shearing, laceration/transection, and acute stretch) in which the physical force is directly imparted to the spinal cord, disrupting axons, blood vessels, and neural-cell membranes. After the primary injury, a cascade of secondary injury events is initiated which expands the zone of neural tissue damage and exacerbate neurological deficits and outcomes. Secondary injury is a progressive condition characterized by pro-inflammatory cytokines, reactive oxygen species, DNA/protein/lipid oxidative damage, excitatory aminoacids such as glutamate, loss of ionic homeostasis, mitochondrial dysfunction and cell death [19, 20, 21]. As mentioned before, mechanical compression of the spinal cord following injury can impair blood flow causing ischemia and an expanded zone of neural tissue injury. Therefore, early surgical decompression is used after SCI to improve vascular supply to the injured area as well as neurobehavioral deficits [22]. Methylprednisolone (MP), a potent synthetic glucocorticoid which upregulates anti-inflammatory cytokine release, has been widely used for SCI management. However, infections are a devastating side effect that may lead to severe pneumonia and sepsis, outweighing the potential neurological benefits [23]. Lastly, blood pressure augmentation is a current strategy in the SCI field. This strategy has emerged to neuroprotect damaged tissue by enhancing perfussion. In addition to these strategies, several neuroprotective therapies targeting key components of the secondary injury phase have emerged in the SCI field. Furthermore, due to the widely recognized difficult regeneration of the adult mammalian central nervous system (CNS), including the spinal cord, the primary and secondary phases of the SCI lead to a progressive loss of neurological function overtime. However, recent progress in the field of SCI research has demonstrated that the CNS has an inherent regenerative capacity. Consequently, while neuroprotective interventions might have a great benefit in the acute phase of injury, the vast majority of SCI patients are in the chronic stage. Neuroregenerative strategies have emerged to facilitate neuronal regrowth in the chronic stage of injury [24].


3. Neuroprotective strategies

Neuroprotective agents aim to reduce secondary insults to the injured spinal cord. Multiple approaches have been studied, and many others are currently under investigation [25]. In fact, the ability of pharmacological agents to limit secondary biochemical damage and cell death has been well established not only in SCI models but also in stroke and head injury [26].

3.1 Pharmacological therapies

3.1.1 Methylprednisolone

MP is one of the most commonly used pharmacological agents due to its anti-inflammatory effects [27]. However, the beneficial effects of MP administration in the setting of acute SCI are outweighed by the risk of significant complications associated to steroids [28].

3.1.2 Riluzole

Riluzole is a benzothiazole sodium channel blocker that protects against excitotoxic cell death by restricting the presynaptic release of glutamate [29]. It is currently approved by the US Food and Drug Administration (FDA) for the treatment of amyotrophic lateral sclerosis [30]. Clinical trials are currently ongoing for investigating riluzole in the setting of acute SCI [31].

3.1.3 Minocycline

Minocycline is a tetracycline-class antibiotic that has demonstrated neuroprotective properties in preclinical models of SCI [32]. A phase II clinical trial demonstrated that early minocycline administration may improve motor recovery in patients with acute SCI [33].

3.1.4 GM-1 ganglioside

GM-1 is a glycosphingolipid found in cell membranes with the ability to enhance neurite growth and nerve regeneration [34]. However, clinical trials in SCI patients found no statistically significant improvement with GM-1 [35].

3.1.5 Fibroblast growth factor-analogue

Fibroblast growth factor (FGF) is a protein found to be neuroprotective against excitotoxicity [36]. A FGF analogue called SUN 13837 was evaluated in a phase I/II clinical trial with results pending publication [25].

3.1.6 Granulocyte colony-stimulating factor

Granulocyte colony-stimulating factor (G-CSF) is found to promote cell survival and inhibit inflammatory cytokine expression [37]. Two recent nonrandomized phase I/IIa clinical trials showed great results in SCI outcomes [38, 39]; however, randomized clinical trials are required to establish the efficacy of G-CSF for SCI.

3.1.7 Hepatocyte growth factor

Hepatocyte growth factor (HGF) increases neuronal survival in SCI models [40]. A phase I/II randomized clinical trial is now underway with results pending publication [41].

3.2 Non-pharmacological therapies

3.2.1 Therapeutic hypothermia

Therapeutic hypothermia (TH; 32°-34° C) reduces the basal metabolic rate and energy demands of the CNS [42]. TH is effective in reducing the extent of CNS injury in neonatal hypoxic ischemic encephalopathy as well as after cardiac arrest [43, 44]. Small studies in SCI patients exposed to TH showed a trend towards neurological recovery [45, 46]. Therefore, these promising results led to a phase II/III clinical trial named “The Acute Rapid Cooling Therapy for Injuries of the Spinal Cord”, which has been planned to assess efficacy [25].

3.2.2 Cerebrospinal fluid drainage

Cerebrospinal fluid drainage objective is to prevent spinal cord hypoperfusion in the postinjury period by lowering the intrathecal pressure [47]. A phase IIb clinical trial evaluating mean arterial pressure elevation with cerebrospinal drainage in SCI has been completed with results pending publication.


4. Neuroregenerative strategies

Neuroregenerative strategies aim to restore neurological function [48]. Chronic SCI sets an excellent example because there are currently no interventions to restore body functions after injury. However, due to the inherent and limited ability of the CNS to regenerate, chronic SCI involves a great challenge for regenerative medicine [49].

4.1 Pharmacological therapies

4.1.1 Rho-ROCK inhibitor

Cethrin/VX-210 is a direct Rho inhibitor applied intraoperatively using a fibrin carrier to the epidural space [50]. A phase I/IIa clinical trial of patients with cervical or thoracic acute SCI found a significant improvement in long-term motor recovery for cervical patients [51].

4.1.2 Anti-NOGO antibody

Anti-NOGO is a recombinant human antibody against NOGO-A, one of the best-known inhibitors of neurite growth and plasticity in adult CNS. Intrathecal application is well tolerated in humans; however, efficacy trials are still needed to consider anti-NOGO antibodies for SCI patients [52].

4.2 Non-pharmacological therapies

4.2.1 Spinal cord stimulation

Spinal cord stimulation (SCS) involves the application of electrical stimulus to generate muscle contractions that allows for functional limb use. SCS has been successfully applied to improve ambulatory ability in patients with incomplete SCI [31]. Moreover, a small human study has shown that SCS combined with rehabilitation provides functional recovery of voluntary lower extremity movement in the chronic phase of SCI [53].

4.3 Cell therapies

Stem cell-based regenerative therapy has many roles in SCI recovery, including modulating the inflammatory response, providing trophic support, and regenerating axons into lost neural circuits [54]. Early research in this field used embryonic stem cells (ESCs), however, ethical concerns led to the introduction of other types of stem cell populations. In fact, adult tissue-derived stem cells, specifically bone marrow-derived cells, have emerged as a leading transplantable cell type for many CNS disorders [55]. Mesenchymal stem cells, olfactory ensheathing cells, Schwann cells, neural stem cells, and oligodendrocyte progenitor cells have been evaluated in phase I/II clinical trials of SCI and have shown promising results [31].

4.4 Biomaterials

The cascade of secondary events following acute injury to the spinal cord results in demyelination, axonal degeneration, and cavitation formation. Therefore, regeneration is hindered by the lack of substrate to support cell migration and axonal growth [56, 57]. The development of tissue engineering technology has opened up new avenues for treating SCI. The main strategy of tissue engineering is to inoculate living cells on extracellular matrix substitutes (biomaterial scaffolds) that can provide a physical structure for cell growth and differentiation, as well as to guide the growth of transplanted cells and promote axonal regeneration of residual neurons [58].

The Neuro-Spinal Scaffold (InVivo Therapeutics Corp, Cambridge, Massachusetts) is a proprietary bioresorbable polymer scaffold that promotes appositional healing, spares white matter, decreases post-traumatic cyst formation, and improves functional recovery in animal models of SCI. A pilot study evaluating the safety of Neuro-Spinal Scaffold implantation has completed recruitment and is currently in the follow-up phase. Moreover, a case report of the first patient to undergo implantation of the Neuro-Spinal Scaffold as part of this trial has been published previously. The patient was a 25-year-old man with a T11–12 fracture-dislocation following a motocross accident. At 3 months after implantation, neurological function had improved, and no complications were seen during the follow-up [31, 59].


5. Exoskeleton

In the past decade, research in SCI rehabilitation has expanded to include robotic devices that initiate or augment movement. These robotic devices are used with two goals: to enhance recovery through functional movement and to act as a mobility aid beyond orthoses and wheelchairs [60]. In fact, exoskeleton training has been developed as a rehabilitation tool and is approved for the rehabilitation of individuals with SCI. Several studies have shown that robotic exoskeleton gait training has positive effects in terms of spasticity and pain reduction, as well as improved gait function without physical assistance [61, 62, 63, 64, 65, 66].

Robotic devices may offer the greatest advantages for patients with incomplete SCI, turning measurable but functionally insignificant motor function into true mobility and independence. However, the global effects of restoring motion to the skeleton and joints in terms of cardiovascular benefits, prevention of contractures, osteoclastic activity, and psychological health have not yet been measured [67].


6. Conclusion

Significant advances over the past decades have decrease the morbidity and mortality following SCI. Unfortunately, these advances have not impacted on the majority of patients affected by SCI, decreasing long-term health and quality of life. Current treatment options for SCI are restricted to systemic delivery of MP, early surgical decompression, and rehabilitation, all of which result in minimal functional recovery. Neuroprotection as well as neuroregeneration are our current targets for both pharmacological and non-pharmacological therapies; however, further research is still needed to find the best option for SCI patients.


  1. 1. Van Den Berg MEL, Castellote JM, Mahillo-Fernandez I, De Pedro-Cuesta J. Incidence of spinal cord injury worldwide: A systematic review. Neuroepidemiology. 2010;34(3):184-92.
  2. 2. McKinley WO, Seel RT, Hardman JT. Nontraumatic spinal cord injury: Incidence, epidemiology, and functional outcome. Arch Phys Med Rehabil. 1999;80(6):619-23.
  3. 3. Alizadeh A, Dyck SM, Karimi-Abdolrezaee S. Traumatic Spinal Cord Injury: An Overview of Pathophysiology, Models and Acute Injury Mechanisms. Front Neurol. 2019;10(March):1-25.
  4. 4. Ackery A, Tator C, Krassioukov A. A global perspective on spinal cord injury epidemiology. J Neurotrauma. 2004;21(10):1355-70.
  5. 5. Rahimi-Movaghar V, Sayyah MK, Akbari H, Khorramirouz R, Rasouli MR, Moradi-Lakeh M, et al. Epidemiology of traumatic spinal cord injury in developing countries: A systematic review. Neuroepidemiology. 2013;41(2):65-85.
  6. 6. Shin JC, Kim DH, Yu SJ, Yang HE, Yoon SY. Epidemiologic change of patients with spinal cord injury. Ann Rehabil Med. 2013;37(1):50-6.
  7. 7. Mahnig S, Landmann G, Stockinger L, Opsommer E. Pain assessment according to the International Spinal Cord Injury Pain classification in patients with spinal cord injury referred to a multidisciplinary pain center. Spinal Cord [Internet]. 2016;54(10):809-15. Available from:
  8. 8. Giangregorio L, McCartney N. Bone loss and muscle atrophy in spinal cord injury: epidemiology, fracture prediction, and rehabilitation strategies. J Spinal Cord Med. 2006;29(5):489-500.
  9. 9. Krassioukov A V., Furlan JC, Fehlings MG. Medical co-morbidities, secondary complications, and mortality in elderly with acute spinal cord injury. J Neurotrauma. 2003;20(4):391-9.
  10. 10. Hou S, Rabchevsky AG. Autonomic consequences of spinal cord injury. Compr Physiol. 2014;4(4):1419-53.
  11. 11. Peterson MD, Kamdar N, Whitney DG, Ng S, Chiodo A, Tate DG. Psychological morbidity and chronic disease among adults with nontraumatic spinal cord injuries: a cohort study of privately insured beneficiaries. Spine J [Internet]. 2019;19(10):1680-6. Available from:
  12. 12. Lourenco L, Blanes L, Salomé GM, Ferreira LM. Quality of life and self-esteem in patients with paraplegia and pressure ulcers: A controlled cross-sectional study. J Wound Care. 2014;23(6):331-7.
  13. 13. Duzgun Celik H, Cagliyan Turk A, Sahin F, Yilmaz F, Kuran B. Comparison of disability and quality of life between patients with pediatric and adult onset paraplegia. J Spinal Cord Med. 2018;41(6):645-52.
  14. 14. Kawanishi CY, Greguol M. Physical activity, quality of life, and functional autonomy of adults with spinal cord injuries. Adapt Phys Act Q. 2013;30(4):317-37.
  15. 15. Kalyani HHN, Dassanayake S, Senarath U. Effects of paraplegia on quality of life and family economy among patients with spinal cord injuries in selected hospitals of Sri Lanka. Spinal Cord [Internet]. 2015;53(6):446-50. Available from:
  16. 16. Burns AS, O’Connell C. The challenge of spinal cord injury care in the developing world. J Spinal Cord Med. 2012;35(1):3-8.
  17. 17. Cripps RA, Lee BB, Wing P, Weerts E, MacKay J, Brown D. A global map for traumatic spinal cord injury epidemiology: Towards a living data repository for injury prevention. Spinal Cord [Internet]. 2011;49(4):493-501. Available from:
  18. 18. Norenberg MD, Smith J, Marcillo A. The Pathology of Human Spinal Cord Injury: Defining the Problems. J Neurotrauma. 2004;21(4):429-40.
  19. 19. Ahuja CS, Nori S, Tetreault L, Wilson J, Kwon B, Harrop J, et al. Traumatic Spinal Cord Injury-Repair and Regeneration. Neurosurgery. 2017;80(3):S9-22.
  20. 20. Venkatesh K, Ghosh SK, Mullick M, Manivasagam G, Sen D. Spinal cord injury: pathophysiology, treatment strategies, associated challenges, and future implications. Cell Tissue Res. 2019;377(2):125-51.
  21. 21. McDonald JW, Sadowsky C. Spinal-cord injury. Lancet [Internet]. 2002 Feb;359(9304):417-25. Available from:
  22. 22. Batchelor PE, Wills TE, Skeers P, Battistuzzo CR, Macleod MR, Howells DW, et al. Meta-Analysis of Pre-Clinical Studies of Early Decompression in Acute Spinal Cord Injury: A Battle of Time and Pressure. PLoS One. 2013;8(8):1-12.
  23. 23. Bracken MB. Steroids for acute spinal cord injury. Cochrane Database Syst Rev [Internet]. 2012 Jan 18;4(3):179-80. Available from:
  24. 24. Wilson JR, Forgione N, Fehlings MG. Emerging therapies for acute traumatic spinal cord injury. Cmaj. 2013;185(6):485-92.
  25. 25. Rouanet C, Reges D, Rocha E, Gagliardi V, Silva GS. Traumatic spinal cord injury: current concepts and treatment update. Arq Neuropsiquiatr [Internet]. 2017 Jun;75(6):387-93. Available from:
  26. 26. Faden AI, Stoica B. Neuroprotection. Arch Neurol [Internet]. 2007 Jun 1;64(6):794. Available from:
  27. 27. Kim YH, Ha KY, Kim S Il. Spinal cord injury and related clinical trials. CiOS Clin Orthop Surg. 2017;9(1):1-9.
  28. 28. Kirke Rogers W, Todd M. Acute spinal cord injury. Best Pract Res Clin Anaesthesiol [Internet]. 2016;30(1):27-39. Available from:
  29. 29. Azbill RD, Mu X, Springer JE. Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes. Brain Res. 2000;871(2):175-80.
  30. 30. Bhatt JM, Gordon PH. Current clinical trials in amyotrophic lateral sclerosis. Expert Opin Investig Drugs [Internet]. 2007 Aug 9;16(8):1197-207. Available from:
  31. 31. Badhiwala JH, Ahuja CS, Fehlings MG. Time is spine: A review of translational advances in spinal cord injury. J Neurosurg Spine. 2019;30(1):1-18.
  32. 32. Yune TY, Lee JY, Jung GY, Kim SJ, Jiang MH, Kim YC, et al. Minocycline alleviates death of oligodendrocytes by inhibiting pro-nerve growth factor production in microglia after spinal cord injury. J Neurosci. 2007;27(29):7751-61.
  33. 33. Casha S, Zygun D, McGowan MD, Bains I, Yong VW, John Hurlbert R. Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain. 2012;135(4):1224-36.
  34. 34. Imanaka T, Hukuda S, Maeda T. The role of GM1-ganglioside in the injured spinal cord of rats: An immunohistochemical study using GM1-antisera. J Neurotrauma. 1996;13(3):163-70.
  35. 35. Geisler FH, Coleman WP, Grieco G, Poonian D. The Sygen® multicenter acute spinal cord injury study. Spine (Phila Pa 1976). 2001;26(24 SUPPL.):87-98.
  36. 36. Siddiqui AM, Khazaei M, Fehlings MG. Translating mechanisms of neuroprotection, regeneration, and repair to treatment of spinal cord injury [Internet]. 1st ed. Vol. 218, Progress in Brain Research. Elsevier B.V.; 2015. 15-54 p. Available from:
  37. 37. Nishio Y, Koda M, Kamada T, Someya Y, Kadota R, Mannoji C, et al. Granulocyte colony-stimulating factor attenuates neuronal death and promotes functional recovery after spinal cord injury in mice. J Neuropathol Exp Neurol. 2007;66(8):724-31.
  38. 38. Takahashi H, Yamazaki M, Okawa A, Sakuma T, Kato K, Hashimoto M, et al. Neuroprotective therapy using granulocyte colony-stimulating factor for acute spinal cord injury: A phase I/IIa clinical trial. Eur Spine J. 2012;21(12):2580-7.
  39. 39. Kamiya K, Koda M, Furuya T, Kato K, Takahashi H, Sakuma T, et al. Neuroprotective therapy with granulocyte colony-stimulating factor in acute spinal cord injury: a comparison with high-dose methylprednisolone as a historical control. Eur Spine J. 2015;24(5):963-7.
  40. 40. Kitamura K, Fujiyoshi K, Yamane J ichi, Toyota F, Hikishima K, Nomura T, et al. Human hepatocyte growth factor promotes functional recovery in primates after spinal cord injury. PLoS One. 2011;6(11).
  41. 41. Kitamura K, Nagoshi N, Tsuji O, Matsumoto M, Okano H, Nakamura M. Application of hepatocyte growth factor for acute spinal cord injury: The road from basic studies to human treatment. Int J Mol Sci. 2019;20(5).
  42. 42. Dietrich WD, Levi AD, Wang M, Green BA. Hypothermic Treatment for Acute Spinal Cord Injury. Neurotherapeutics. 2011;8(2):229-39.
  43. 43. Dehaes M, Aggarwal A, Lin PY, Rosa Fortuno C, Fenoglio A, Roche-Labarbe N, et al. Cerebral oxygen metabolism in neonatal hypoxic ischemic encephalopathy during and after therapeutic hypothermia. J Cereb Blood Flow Metab. 2014;34(1):87-94.
  44. 44. Holzer M, Sterz F, Darby JM, Padosch SA, Kern KB, Böttiger BW, et al. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549-56.
  45. 45. Levi AD, Green BA, Wang MY, Dietrich WD, Brindle T, Vanni S, et al. Clinical application of modest hypothermia after spinal cord injury. J Neurotrauma. 2009;26(3):407-15.
  46. 46. Dididze M, Green BA, Dalton Dietrich W, Vanni S, Wang MY, Levi AD. Systemic hypothermia in acute cervical spinal cord injury: A case-controlled study. Spinal Cord [Internet]. 2013;51(5):395-400. Available from:
  47. 47. Kwon BK, Curt AN, Belanger LM, Bernardo A, Chan D, Markez JA, et al. Intrathecal pressure monitoring and cerebrospinal fluid drainage in acute spinal cord injury: A prospective randomized trial - Clinical article. J Neurosurg Spine. 2009;10(3):181-93.
  48. 48. Ahuja CS, Fehlings M. Concise Review: Bridging the Gap: Novel Neuroregenerative and Neuroprotective Strategies in Spinal Cord Injury. Stem Cells Transl Med [Internet]. 2016 Jul;5(7):914-24. Available from:
  49. 49. Dalamagkas K, Tsintou M, Seifalian A, Seifalian AM. Translational regenerative therapies for chronic spinal cord injury. Int J Mol Sci. 2018;19(6):1-17.
  50. 50. Forgione N, Fehlings MG. Rho-ROCK inhibition in the treatment of spinal cord injury. World Neurosurg [Internet]. 2014;82(3):E535-9. Available from:
  51. 51. Fehlings MG, Theodore N, Harrop J, Maurais G, Kuntz C, Shaffrey CI, et al. A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury. J Neurotrauma. 2011;28(5):787-96.
  52. 52. Kucher K, Johns D, Maier D, Abel R, Badke A, Baron H, et al. First-in-man intrathecal application of neurite growth-promoting anti-nogo- a antibodies in acute spinal cord injury. Neurorehabil Neural Repair. 2018;32(6-7):578-89.
  53. 53. Angeli CA, Edgerton VR, Gerasimenko YP, Harkema SJ. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain. 2014;137(5):1394-409.
  54. 54. Assinck P, Duncan GJ, Hilton BJ, Plemel JR, Tetzlaff W. Cell transplantation therapy for spinal cord injury. Nat Neurosci. 2017;20(5):637-47.
  55. 55. Incontri Abraham D, Gonzales M, Ibarra A, Borlongan C V. Stand alone or join forces? Stem cell therapy for stroke. Vol. 19, Expert Opinion on Biological Therapy. Taylor and Francis Ltd; 2019. p. 25-33.
  56. 56. Mothe AJ, Tam RY, Zahir T, Tator CH, Shoichet MS. Repair of the injured spinal cord by transplantation of neural stem cells in a hyaluronan-based hydrogel. Biomaterials [Internet]. 2013;34(15):3775-83. Available from:
  57. 57. Itosaka H, Kuroda S, Shichinohe H, Yasuda H, Yano S, Kamei S, et al. Fibrin matrix provides a suitable scaffold for bone marrow stromal cells transplanted into injured spinal cord: A novel material for CNS tissue engineering. Neuropathology. 2009;29(3):248-57.
  58. 58. Liu S, Xie YY, Wang B. Role and prospects of regenerative biomaterials in the repair of spinal cord injury. Neural Regen Res. 2019;14(8):1352-63.
  59. 59. Theodore N, Hlubek R, Danielson J, Neff K, Vaickus L, Ulich TR, et al. First human implantation of a bioresorbable polymer scaffold for acute traumatic spinal cord injury: A clinical pilot study for safety and feasibility. Neurosurgery. 2016;79(2):E305-12.
  60. 60. Mekki M, Delgado AD, Fry A, Putrino D, Huang V. Robotic Rehabilitation and Spinal Cord Injury: a Narrative Review. Neurotherapeutics. 2018;15(3):604-17.
  61. 61. Baunsgaard CB, Nissen UV, Brust AK, Frotzler A, Ribeill C, Kalke YB, et al. Exoskeleton gait training after spinal cord injury: An exploratory study on secondary health conditions. J Rehabil Med. 2018;50(9):806-13.
  62. 62. Stampacchia G, Rustici A, Bigazzi S, Gerini A, Tombini T, Mazzoleni S. Walking with a powered robotic exoskeleton: Subjective experience, spasticity and pain in spinal cord injured persons. NeuroRehabilitation. 2016;39(2):277-83.
  63. 63. Grasmücke D, Zieriacks A, Jansen O, Fisahn C, Sczesny-Kaiser M, Wessling M, et al. Against the odds: What to expect in rehabilitation of chronic spinal cord injury with a neurologically controlled Hybrid Assistive Limb exoskeleton. A subgroup analysis of 55 patients according to age and lesion level. Neurosurg Focus. 2017;42(5).
  64. 64. Bach Baunsgaard C, Vig Nissen U, Katrin Brust A, Frotzler A, Ribeill C, Kalke YB, et al. Gait training after spinal cord injury: Safety, feasibility and gait function following 8 weeks of training with the exoskeletons from Ekso Bionics article. Spinal Cord [Internet]. 2018;56(2):106-16. Available from:
  65. 65. Miller L, Zimmermann A, Herbert W. Clinical effectiveness and safety of powered exoskeleton-assisted walking in patients with spinal cord injury: systematic review with meta-analysis. Med Devices Evid Res [Internet]. 2016 Mar;455. Available from:
  66. 66. Wu CH, Mao HF, Hu JS, Wang TY, Tsai YJ, Hsu WL. The effects of gait training using powered lower limb exoskeleton robot on individuals with complete spinal cord injury. J Neuroeng Rehabil. 2018;15(1):1-10.
  67. 67. Ghobrial GM, Wang MY. The next generation of powered exoskeleton use in spinal cord injury. Neurosurg Focus. 2017;42(5):1-2.

Written By

Diego Incontri-Abraham and José Juan Antonio Ibarra Arias

Published: May 12th, 2021