The Archives of Bone and Joint Surgery

The Archives of Bone and Joint Surgery

Recent Advances in the Treatment of Spinal Cord Injury

Document Type : CURRENT CONCEPTS REVIEW

Authors
Davood Yari 1
Arezoo Saberi 2
Zahra Salmasi 3
Seyed Alireza Ghoreishi 4
Leila Etemad 5
Jebrail Movaffagh  6
Babak Ganjeifar 7
1 Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran - Orthopedic Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
2 Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
3 Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran - Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
4 Orthopedic Research Center, Mashhad University of Medical Sciences, Mashhad, Iran - Department of Orthopedic Surgery, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
5 Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
6 Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran - Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
7 Department of Neurosurgery, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
10.22038/abjs.2023.73944.3424
Abstract
Spinal cord injury (SCI) is a complex, multifaceted, progressive, and yet incurable complication that 
can cause irreversible damage to the individual, family, and society. In recent years strategies for the 
management and rehabilitation of SCI besides axonal regeneration, remyelination, and neuronal 
plasticity of the injured spinal cord have significantly improved. Although most of the current research 
and therapeutic advances have been made in animal models, so far, no specific and complete treatment 
has been reported for SCI in humans. The failure to treat this complication has been due to the inherent 
neurological complexity and the structural, cellular, molecular, and biochemical characteristics of spinal 
cord injury. In this review, in addition to elucidating the causes of spinal cord injury from a molecular 
and pathophysiological perspective, the complexity and drawbacks of neural regeneration that lead to 
the failure in SCI treatment are described. Also, recent advances and cutting -edge strategies in most 
areas of SCI treatment are presented. 
 Level of evidence: I
Keywords
Combination therapy
Neural tissue engineering
Neuron
SCI
Spinal cord injury
Subjects
  1. Bajjig A, Cayetanot F, Taylor JA, Bodineau L, Vivodtzev I. Serotonin 1A Receptor Pharmacotherapy and Neuroplasticity in Spinal Cord Injury. Pharmaceuticals (Basel). 2022; 15(4).doi:10.3390/ph15040460.
  2. Adigun OO, Reddy V, Varacallo M. Anatomy, Back, Spinal Cord. StatPearls. 2022.
  3. Bilchak JN, Caron G, Cote MP. Exercise-Induced Plasticity in Signaling Pathways Involved in Motor Recovery after Spinal Cord Injury. Int J Mol Sci. 2021; 22(9).doi:10.3390/ijms22094858.
  4. Ebrahimpour A, Razi M, Mortazavi SJ, et al. Job satisfaction, Career Burnout, and Work-Related Well-Being Prevalence among Orthopedic Surgeons: A Nationwide Study. Arch Bone Jt Surg. 2023; 11(4):293-300. doi:10.22038/ABJS.2022.66683.3180.
  5. Khan YS, Lui F. Neuroanatomy, Spinal Cord. InStatPearls [Internet] 2022. StatPearls Publishing.
  6. Ebrahimzadeh MH, Makhmalbaf H, Soltani-Moghaddas SH, Mazloumi SM. The spinal cord injury quality-of-life-23 questionnaire, Iranian validation study. J Res Med Sci. 2014; 19(4):349-54.
  7. Ebrahimzadeh MH, Shojaei BS, Golhasani-Keshtan F, Soltani-Moghaddas SH, Fattahi AS, Mazloumi SM. Quality of life and the related factors in spouses of veterans with chronic spinal cord injury. Health Qual Life Outcomes. 2013; 11:48. doi:10.1186/1477-7525-11-48.
  8. Neural Injury and Repair Research Group. Available at: https://neurosciences.ucsd.edu/research/interest-groups/neural-injury-repair.html. Accessed, 2021.
  9. Ebrahimzadeh MH, Soltani-Moghaddas SH, Birjandinejad A, Omidi-Kashani F, Bozorgnia S. Quality of life among veterans with chronic spinal cord injury and related variables. Arch Trauma Res. 2014; 3(2):e17917. doi:10.5812/atr.17917.
  10. Barbiellini Amidei C, Salmaso L, Bellio S, Saia M. Epidemiology of traumatic spinal cord injury: a large population-based study. Spinal Cord. 2022; 60(9):812-819.doi:10.1038/s41393-022-00795-w.
  11. Khadour FA, Khadour YA, Meng L, Lixin C, Xu T. Epidemiological features of traumatic spinal cord injury in Wuhan, China. J Orthop Surg Res. 2023; 18(1):72. doi:10.1186/s13018-023-03554-6.
  12. Ebrahimzadeh MH, Golhasani-Keshtan F, Shojaee BS. Correlation between health-related quality of life in veterans with chronic spinal cord injury and their caregiving spouses. Arch Trauma Res. 2014; 3(4):e16720. doi:10.5812/atr.16720.
  13. Abdelrahman S, Ireland A, Winter EM, Purcell M, Coupaud S. Osteoporosis after spinal cord injury: aetiology, effects and therapeutic approaches. J Musculoskelet Neuronal Interact. 2021; 21(1):26-50.
  14. Ebrahimzadeh MH, Shojaee BS, Golhasani-Keshtan F, Moharari F, Kachooei AR, Fattahi AS. Depression, anxiety and quality of life in caregiver spouses of veterans with chronic spinal cord injury. Iran J Psychiatry. 2014; 9(3):133-6.
  15. Lv B, Zhang X, Yuan J, et al. Biomaterial-supported MSC transplantation enhances cell-cell communication for spinal cord injury. Stem Cell Res Ther. 2021; 12(1):36. doi:10.1186/s13287-020-02090-y.
  16. Domingues HS, Portugal CC, Socodato R, Relvas JB. Corrigendum: Oligodendrocyte, Astrocyte and Microglia Crosstalk in Myelin Development, Damage, and Repair. Front Cell Dev Biol. 2016; 4:79. doi:10.3389/fcell.2016.00079.
  17. Uchida K, Nakamura M, Ozawa H, Katoh S, Toyama Y, eds. Neuroprotection and regeneration of the spinal cord. 1st ed. Springer Tokyo; 2014.
  18. Lescaudron L, Rossignol J, Dunbar GL,eds. Stem Cells and Neurodegenerative Diseases. 1st ed. Routledge Taylor & Francis Group; 2014.
  19. Faridaalee G, Keyghobadi Khajeh F. Serum and Cerebrospinal Fluid Levels of S-100beta Is A Biomarker for Spinal Cord Injury; a Systematic Review and Meta-Analysis. Arch Acad Emerg Med. 2019; 7(1):e19.
  20. Ganjeifar B, Mehrad-Majd H, Barforooshi AG, Baharvahdat H, Zabihyan S, Moradi A. Diagnostic Value of Computed Tomography Angiography in Confirmation of Brain Death. World Neurosurg. 2023:178:e275-e281. doi:10.1016/j.wneu.2023.07.042.
  21. Molinaro F, La Zazzera PL, Ferraris M, Morbidoni G, Zaca D ,  Rinaldis A,  Carpanese F,  Cioffi A,  Naddeo F,  Boccaccini L,  Bergui M. Chapter 4 - MRI as an imaging tool for in vivo noninvasive morphological and (partially) functional examination of injured spinal cord. In: Spinal Cord Injury (SCI) Repair Strategies. 1st ed. Perale G, Rossi F, eds.WP Publishing; 2020.
  22. Seo JH, Kim HJ, Lee KY, Wang L, Park JW. The Prognostic Factors of Neurologic Recovery in Spinal Cord Injury. J Korean Soc Spine Surg. 2015; 22(1):1-7.
  23. Beattie MS. Inflammation and apoptosis: linked therapeutic targets in spinal cord injury. Trends Mol Med. 2004; 10(12):580-3. doi:10.1016/j.molmed.2004.10.006.
  24. Rowland JW, Hawryluk GW, Kwon B, Fehlings MG. Current status of acute spinal cord injury pathophysiology and emerging therapies: promise on the horizon. Neurosurg Focus. 2008; 25(5):E2. doi:10.3171/FOC.2008.25.11.E2.
  25. Seblani M, Decherchi P, Brezun JM. Edema after CNS Trauma: A Focus on Spinal Cord Injury. Int J Mol Sci. 2023; 24(8) doi: 10.3390/ijms24087159.
  26. Shi Z, Yuan S, Shi L, et al. Programmed cell death in spinal cord injury pathogenesis and therapy. Cell Prolif. 2021; 54(3):e12992. doi:10.1111/cpr.12992.
  27. Anjum A, Yazid MD, Fauzi Daud M, et al. Spinal Cord Injury: Pathophysiology, Multimolecular Interactions, and Underlying Recovery Mechanisms. Int J Mol Sci. 2020; 21(20). doi:10.3390/ijms21207533.
  28. Hu X, Xu W, Ren Y, et al. Spinal cord injury: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2023; 8(1):245. doi:10.1038/s41392-023-01477-6.
  29. Clifford T, Finkel Z, Rodriguez B, Joseph A, Cai L. Current Advancements in Spinal Cord Injury Research-Glial Scar Formation and Neural Regeneration. Cells. 2023; 12(6) doi: 10.3390/cells12060853.
  30. Anderson MA, Burda JE, Ren Y, et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature. 2016; 532(7598):195-200. doi:10.1038/nature17623.
  31. Carelli S, Giallongo T, Rey F, et al. Neuroprotection, Recovery of Function and Endogenous Neurogenesis in Traumatic Spinal Cord Injury Following Transplantation of Activated Adipose Tissue. Cells. 2019; 8(4).doi:10.3390/cells8040329.
  32. Yari D, Ehsanbakhsh Z, Validad MH, Langroudi FH. Association of TIMP-1 and COL4A4 Gene Polymorphisms with Keratoconus in an Iranian Population. J Ophthalmic Vis Res. 2020; 15(3):299-307. doi:10.18502/jovr.v15i3.7448.
  33. Zhang Q, Shi B, Ding J, et al. Polymer scaffolds facilitate spinal cord injury repair. Acta Biomater. 2019; 88:57-77. doi:10.1016/j.actbio.2019.01.056.
  34. Yousefifard M, Vazirizadeh-Mahabadi MH, Haghani L, et al. Early General Hypothermia Improves Motor Function after Spinal Cord Injury in Rats; a Systematic Review and Meta-Analysis. Arch Acad Emerg Med. 2020; 8(1):e80.
  35. 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):125-151. doi:10.1007/s00441-019-03039-1.
  36. Lee BJ, Jeong JH. Review: Steroid Use in Patients with Acute Spinal Cord Injury and Guideline Update. Korean J Neurotrauma. 2022; 18(1):22-30. doi:10.13004/kjnt.2022.18.e21.
  37. Zhang Y, Al Mamun A, Yuan Y, et al. Acute spinal cord injury: Pathophysiology and pharmacological intervention (Review). Mol Med Rep. 2021; 23(6) doi:10.3892/mmr.2021.12056.
  38. Li Y, Gu R, Zhu Q, Liu J. Changes of Spinal Edema and Expression of Aquaporin 4 in Methylprednisolone-treated Rats with Spinal Cord Injury. Ann Clin Lab Sci. 2018; 48(4):453-459.
  39. Roohbakhsh A, Etemad L, Karimi G. Resolvin D1: A key endogenous inhibitor of neuroinflammation. Biofactors. 2022; 48(5):1005-1026. doi:10.1002/biof.1891.
  40. Park A, Anderson D, Battaglino RA, Nguyen N, Morse LR. Ibuprofen use is associated with reduced C-reactive protein and interleukin-6 levels in chronic spinal cord injury. J Spinal Cord Med. 2022; 45(1):117-125. doi:10.1080/10790268.2020.1773029.
  41. Hayta E, Elden H. Acute spinal cord injury: A review of pathophysiology and potential of non-steroidal anti-inflammatory drugs for pharmacological intervention. J Chem Neuroanat. 2018; 87:25-31. doi:10.1016/j.jchemneu.2017.08.001.
  42. Roohbakhsh A, Moshiri M, Salehi Kakhki A, Iranshahy M, Amin F, Etemad L. Thymoquinone abrogates methamphetamine-induced striatal neurotoxicity and hyperlocomotor activity in mice. Res Pharm Sci. 2021; 16(4):391-399. doi:10.4103/1735-5362.319577.
  43. Fehlings MG, Wilson JR, Tetreault LA, et al. A Clinical Practice Guideline for the Management of Patients with Acute Spinal Cord Injury: Recommendations on the Use of Methylprednisolone Sodium Succinate. Global Spine J. 2017; 7(3 Suppl):203S-211S. doi:10.1177/2192568217703085.
  44. Kupfer M, Formal CS. Non-opioid pharmacologic treatment of chronic spinal cord injury-related pain. J Spinal Cord Med. 2022; 45(2):163-172. doi:10.1080/10790268.2020.1730109.
  45. Yousefifard M, Hashemi B, Forouzanfar MM, Khatamian Oskooi R, Madani Neishaboori A, Jalili Khoshnoud R. Ultra-early Spinal Decompression Surgery Can Improve Neurological Outcome of Complete Cervical Spinal Cord Injury; a Systematic Review and Meta-analysis. Arch Acad Emerg Med. 2022; 10(1):e11. doi:10.22037/aaem.v10i1.1471.
  46. Ma Y, Zhu Y, Zhang B, Wu Y, Liu X, Zhu Q. The Impact of Urgent (<8 Hours) Decompression on Neurologic Recovery in Traumatic Spinal Cord Injury: A Meta-Analysis. World Neurosurg. 2020; 140:e185-e194. doi:10.1016/j.wneu.2020.04.230.
  47. Ter Wengel PV, Martin E, De Witt Hamer PC, et al. Impact of Early (<24 h) Surgical Decompression on Neurological Recovery in Thoracic Spinal Cord Injury: A Meta-Analysis. J Neurotrauma. 2019; 36(18):2609-2617. doi:10.1089/neu.2018.6277.
  48. Badhiwala JH, Wilson JR, Witiw CD, et al. The influence of timing of surgical decompression for acute spinal cord injury: a pooled analysis of individual patient data. Lancet Neurol. 2021; 20(2):117-126. doi:10.1016/S1474-4422(20)30406-3.
  49. Gu X, Ding F, Yang Y, Liu J. Construction of tissue engineered nerve grafts and their application in peripheral nerve regeneration. Prog Neurobiol. 2011; 93(2):204-30. doi:10.1016/j.pneurobio.2010.11.002.
  50. Leckenby JI, Furrer C, Haug L, Juon Personeni B, Vogelin E. A Retrospective Case Series Reporting the Outcomes of Avance Nerve Allografts in the Treatment of Peripheral Nerve Injuries. Plast Reconstr Surg. 2020; 145(2):368e-381e. doi:10.1097/PRS.0000000000006485.
  51. Liu Y, Xie JX, Niu F, et al. Surgical intervention combined with weight-bearing walking training improves neurological recoveries in 320 patients with clinically complete spinal cord injury: a prospective self-controlled study. Neural Regen Res. 2021; 16(5):820-829. doi:10.4103/1673-5374.297080.
  52. Mansour NM, Pino IP, Freeman D, et al. Advances in Epidural Spinal Cord Stimulation to Restore Function after Spinal Cord Injury: History and Systematic Review. J Neurotrauma. 2022; 39(15-16):1015-1029.doi:10.1089/neu.2022.0007.
  53. O'Connell NE, Ferraro MC, Gibson W, et al. Implanted spinal neuromodulation interventions for chronic pain in adults. Cochrane Database Syst Rev. 2021; 12:CD013756. doi:10.1002/14651858.CD013756.pub2.
  54. Qu H, Zhao Y. Advances in tissue state recognition in spinal surgery: a review. Front Med. 2021; 15(4):575-584. doi:10.1007/s11684-020-0816-3.
  55. Shahpari O, Mortazavi J, Ebrahimzadeh MH, Bagheri F, Mousavian A. Role of Hip Arthroscopy in the Treatment of Avascular Necrosis of the Hip: A Systematic Review. Arch Bone Jt Surg. 2022; 10(6):480-489. doi:10.22038/ABJS.2021.58534.2894.
  56. Xiong F, Fu C, Zhang Q, et al. The Effect of Different Acupuncture Therapies on Neurological Recovery in Spinal Cord Injury: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials. Evid Based Complement Alternat Med. 2019; 2019:2371084. doi:10.1155/2019/2371084.
  57. Tang H, Guo Y, Zhao Y, et al. Effects and Mechanisms of Acupuncture Combined with Mesenchymal Stem Cell Transplantation on Neural Recovery after Spinal Cord Injury: Progress and Prospects. Neural Plast. 2020; 2020:8890655. doi:10.1155/2020/8890655.
  58. Zeng YS, Ding Y, Xu HY, et al. Electro-acupuncture and its combination with adult stem cell transplantation for spinal cord injury treatment: A summary of current laboratory findings and a review of literature. CNS Neurosci Ther. 2022; 28(5):635-647. doi:10.1111/cns.13813.
  59. van der Scheer JW, Totosy de Zepetnek JO, Blauwet C, et al. Assessment of body composition in spinal cord injury: A scoping review. PLoS One. 2021; 16(5):e0251142. doi:10.1371/journal.pone.0251142.
  60. Ginis KAM, van der Scheer JW, Latimer-Cheung AE, et al. Correction: Evidence-based scientific exercise guidelines for adults with spinal cord injury: an update and a new guideline. Spinal Cord. 2018; 56(11):1114. doi:10.1038/s41393-018-0194-8.
  61. van der Scheer JW, Goosey-Tolfrey VL, Valentino SE, Davis GM, Ho CH. Functional electrical stimulation cycling exercise after spinal cord injury: a systematic review of health and fitness-related outcomes. J Neuroeng Rehabil. 2021; 18(1):99. doi:10.1186/s12984-021-00882-8.
  62. Lovas J, Tran Y, Middleton J, Bartrop R, Moore N, Craig A. Managing pain and fatigue in people with spinal cord injury: a randomized controlled trial feasibility study examining the efficacy of massage therapy. Spinal Cord. 2017; 55(2):162-166. doi:10.1038/sc.2016.156.
  63. Franz S, Schulz B, Wang H, et al. Management of pain in individuals with spinal cord injury: Guideline of the German-Speaking Medical Society for Spinal Cord Injury. Ger Med Sci. 2019; 17:Doc05. doi:10.3205/00027.1
  64. Palladino L, Ruotolo I, Berardi A, Carlizza A, Galeoto G. Efficacy of aquatic therapy in people with spinal cord injury: a systematic review and meta-analysis. Spinal Cord. 2023; 61(6):317-322. doi:10.1038/s41393-023-00892-4.
  65. Vafaei-Nezhad S, Pour Hassan M, Noroozian M, et al. A Review of Low-Level Laser Therapy for Spinal Cord Injury: Challenges and Safety. J Lasers Med Sci. 2020; 11(4):363-368. doi:10.34172/jlms.2020.59.
  66. Kim J, Kim EH, Lee K, et al. Low-Level Laser Irradiation Improves Motor Recovery after Contusive Spinal Cord Injury in Rats. Tissue Eng Regen Med. 2017; 14(1):57-64. doi:10.1007/s13770-016-0003-4.
  67. Tehrani MR, Nazary-Moghadam S, Zeinalzadeh A, Moradi A, Mehrad-Majd H, Sahebalam M. Efficacy of low-level laser therapy on pain, disability, pressure pain threshold, and range of motion in patients with myofascial neck pain syndrome: a systematic review and meta-analysis of randomized controlled trials. Lasers Med Sci. 2022; 37(9):3333-3341.doi:10.1007/s10103-022-03626-9.
  68. Farid MF, Y SA, Rizk H. Stem cell treatment trials of spinal cord injuries in animals. Auton Neurosci. 2021; 238:102932. doi:10.1016/j.autneu.2021.102932.
  69. Huang L, Fu C, Xiong F, He C, Wei Q. Stem Cell Therapy for Spinal Cord Injury. Cell Transplant. 2021; 30:963689721989266. doi:10.1177/0963689721989266.
  70. Nori S, Nakamura M, Okano H. Plasticity and regeneration in the injured spinal cord after cell transplantation therapy. Prog Brain Res. 2017; 231:33-56. doi:10.1016/bs.pbr.2016.12.007.
  71. Chhabra HS, Sarda K. Clinical translation of stem cell based interventions for spinal cord injury - Are we there yet? Adv Drug Deliv Rev. 2017; 120:41-49. doi:10.1016/j.addr.2017.09.021.
  72. Lowry LE, Herzig MC, Christy BA, et al. Neglected No More: Emerging Cellular Therapies in Traumatic Injury. Stem Cell Rev Rep. 2021; 17(4):1194-1214.doi:10.1007/s12015-020-10086-7.
  73. Takami T, Shimokawa N, Parthiban J, Zileli M, Ali S. Pharmacologic and Regenerative Cell Therapy for Spinal Cord Injury: WFNS Spine Committee Recommendations. Neurospine. 2020; 17(4):785-796. doi:10.14245/ns.2040408.204.
  74. Khan S, Mafi P, Mafi R, Khan W. A Systematic Review of Mesenchymal Stem Cells in Spinal Cord Injury, Intervertebral Disc Repair and Spinal Fusion. Curr Stem Cell Res Ther. 2018; 13(4):316-323. doi:10.2174/1574888X11666170907120030.
  75. Kong D, Feng B, Amponsah AE, et al. hiPSC-derived NSCs effectively promote the functional recovery of acute spinal cord injury in mice. Stem Cell Res Ther. 2021; 12(1):172. doi:10.1186/s13287-021-02217-9.
  76. Zheng W, Li Q, Zhao C, Da Y, Zhang HL, Chen Z. Differentiation of Glial Cells From hiPSCs: Potential Applications in Neurological Diseases and Cell Replacement Therapy. Front Cell Neurosci. 2018; 12:239. doi:10.3389/fncel.2018.00239.
  77. Wang X, Kuang N, Chen Y, et al. Transplantation of olfactory ensheathing cells promotes the therapeutic effect of neural stem cells on spinal cord injury by inhibiting necrioptosis. Aging (Albany NY). 2021; 13(6):9056-9070. doi:10.18632/aging.202758.
  78. Monje PV, Deng L, Xu XM. Human Schwann Cell Transplantation for Spinal Cord Injury: Prospects and Challenges in Translational Medicine. Front Cell Neurosci. 2021; 15:690894. doi:10.3389/fncel.2021.690894.
  79. Beatriz M, Vilaca R, Lopes C. Exosomes: Innocent Bystanders or Critical Culprits in Neurodegenerative Diseases. Front Cell Dev Biol. 2021; 9:635104. doi:10.3389/fcell.2021.635104.
  80. Pishavar E, Oroojalian F, Salmasi Z, Hashemi E, Hashemi M. Recent advances of dendrimer in targeted delivery of drugs and genes to stem cells as cellular vehicles. Biotechnol Prog. 2021; 37(4):e3174. doi:10.1002/btpr.3174.
  81. Upadhyayula PS, Martin JR, Rennert RC, Ciacci JD. Review of operative considerations in spinal cord stem cell therapy. World J Stem Cells. 2021; 13(2):168-176. doi:10.4252/wjsc.v13.i2.168.
  82. Honmou O, Yamashita T, Morita T, et al. Intravenous infusion of auto serum-expanded autologous mesenchymal stem cells in spinal cord injury patients: 13 case series. Clin Neurol Neurosurg. 2021; 203:106565. doi:10.1016/j.clineuro.2021.106565.
  83. Xia Y, Zhu J, Yang R, Wang H, Li Y, Fu C. Mesenchymal stem cells in the treatment of spinal cord injury: Mechanisms, current advances and future challenges. Front Immunol. 2023; 14:1141601. doi:10.3389/fimmu.2023.1141601.
  84. Bartlett RD, Burley S, Ip M, Phillips JB, Choi D. Cell Therapies for Spinal Cord Injury: Trends and Challenges of Current Clinical Trials. Neurosurgery. 2020; 87(4):E456-E472. doi:10.1093/neuros/nyaa149.
  85. Shang Z, Wang R, Li D, et al. Spinal Cord Injury: A Systematic Review and Network Meta-Analysis of Therapeutic Strategies Based on 15 Types of Stem Cells in Animal Models. Front Pharmacol. 2022; 13:819861. doi:10.3389/fphar.2022.819861.
  86. Pang QM, Chen SY, Fu SP, et al. Regulatory Role of Mesenchymal Stem Cells on Secondary Inflammation in Spinal Cord Injury. J Inflamm Res. 2022; 15:573-593. doi:10.2147/JIR.S349572.
  87. Kim BG, Hwang DH, Lee SI, Kim EJ, Kim SU. Stem cell-based cell therapy for spinal cord injury. Cell Transplant. 2007; 16(4):355-64. doi:10.3727/000000007783464885.
  88. Xue W, Shi W, Kong Y, Kuss M, Duan B. Anisotropic scaffolds for peripheral nerve and spinal cord regeneration. Bioact Mater. 2021; 6(11):4141-4160. doi:10.1016/j.bioactmat.2021.04.019.
  89. saberi A, Khodaverdi E, Kamali H, et al. Fabrication and Characterization of Biomimetic Electrospun Cartilage Decellularized Matrix (CDM)/Chitosan Nanofiber Hybrid for Tissue Engineering Applications: Box-Behnken Design for Optimization. Journal of Polymers and the Environment. 2023:1-20.doi:10.1007/s10924-023-03065-9.
  90. Ashammakhi N, Kim HJ, Ehsanipour A, et al. Regenerative Therapies for Spinal Cord Injury. Tissue Eng Part B Rev. 2019; 25(6):471-491. doi:10.1089/ten.TEB.2019.0182.
  91. Elkhenany H, Bonilla P, Giraldo E, et al. A Hyaluronic Acid Demilune Scaffold and Polypyrrole-Coated Fibers Carrying Embedded Human Neural Precursor Cells and Curcumin for Surface Capping of Spinal Cord Injuries. Biomedicines. 2021; 9(12) doi: 10.3390/biomedicines9121928.
  92. Liu S, Sun X, Wang T, et al. Nano-fibrous and ladder-like multi-channel nerve conduits: Degradation and modification by gelatin. Mater Sci Eng C Mater Biol Appl. 2018; 83:130-142. doi:10.1016/j.msec.2017.11.020.
  93. Li R, Liu H, Huang H, et al. Chitosan conduit combined with hyaluronic acid prevent sciatic nerve scar in a rat model of peripheral nerve crush injury. Mol Med Rep. 2018; 17(3):4360-4368. doi:10.3892/mmr.2018.8388.
  94. Martinez-Ramos C, Doblado LR, Mocholi EL, et al. Biohybrids for spinal cord injury repair. J Tissue Eng Regen Med. 2019; 13(3):509-521. doi:10.1002/term.2816.
  95. Licht C, Rose JC, Anarkoli AO, et al. Synthetic 3D PEG-Anisogel Tailored with Fibronectin Fragments Induce Aligned Nerve Extension. Biomacromolecules. 2019; 20(11):4075-4087. doi:10.1021/acs.biomac.9b00891.
  96. Walsh CM, Wychowaniec JK, Brougham DF, Dooley D. Functional hydrogels as therapeutic tools for spinal cord injury: New perspectives on immunopharmacological interventions. Pharmacol Ther. 2022; 234:108043. doi:10.1016/j.pharmthera.2021.108043.
  97. Kubinová Š. Chapter 7 - Soft and rigid scaffolds for spinal cord injury regeneration. In: Spinal Cord Injury (SCI) Repair Strategies. Perale G, Rossi F, eds.Woodhead Publishing; 2020.
  98. Yari D, Movaffagh J, Ebrahimzadeh MH, Saberi A, Qujeq D, Moradi A. Biomimetic ECM-Based Hybrid Scaffold for Cartilage Tissue Engineering Applications. Journal of Polymers and the Environment. 2024:1-9.doi:10.1007/s10924-024-03230-8.
  99. Zhang S, Wang XJ, Li WS, et al. Polycaprolactone/polysialic acid hybrid, multifunctional nanofiber scaffolds for treatment of spinal cord injury. Acta Biomater. 2018; 77:15-27. doi:10.1016/j.actbio.2018.06.038.
  100. Koser DE, Moeendarbary E, Hanne J, Kuerten S, Franze K. CNS cell distribution and axon orientation determine local spinal cord mechanical properties. Biophys J. 2015; 108(9):2137-47. doi:10.1016/j.bpj.2015.03.039.
  101. Hu J, Jin LQ, Selzer ME. Inhibition of central axon regeneration: perspective from chondroitin sulfate proteoglycans in lamprey spinal cord injury. Neural Regen Res. 2022; 17(9):1955-1956. doi:10.4103/1673-5374.335144.
  102. 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):1352-1363. doi:10.4103/1673-5374.253512.
  103. Xiang W, Cao H, Tao H, et al. Applications of chitosan-based biomaterials: From preparation to spinal cord injury neuroprosthetic treatment. Int J Biol Macromol. 2023; 230:123447. doi:10.1016/j.ijbiomac.2023.123447.
  104. Feng C, Deng L, Yong YY, et al. The Application of Biomaterials in Spinal Cord Injury. Int J Mol Sci. 2023; 24(1) doi: 10.3390/ijms24010816.
  105. Wang SX, Lu YB, Wang XX, et al. Graphene and graphene-based materials in axonal repair of spinal cord injury. Neural Regen Res. 2022; 17(10):2117-2125. doi:10.4103/1673-5374.335822.
  106. Luo Y, Fan L, Liu C, et al. An injectable, self-healing, electroconductive extracellular matrix-based hydrogel for enhancing tissue repair after traumatic spinal cord injury. Bioact Mater. 2022; 7:98-111. doi:10.1016/j.bioactmat.2021.05.039.
  107. Luo J, Shi X, Li L, et al. An injectable and self-healing hydrogel with controlled release of curcumin to repair spinal cord injury. Bioact Mater. 2021; 6(12):4816-4829. doi:10.1016/j.bioactmat.2021.05.022.
  108. Bousalis D, McCrary MW, Vaughn N, et al. Decellularized peripheral nerve as an injectable delivery vehicle for neural applications. J Biomed Mater Res A. 2022; 110(3):595-611. doi:10.1002/jbm.a.37312.
  109. Xu Y, Zhou J, Liu C, et al. Understanding the role of tissue-specific decellularized spinal cord matrix hydrogel for neural stem/progenitor cell microenvironment reconstruction and spinal cord injury. Biomaterials. 2021; 268:120596. doi:10.1016/j.biomaterials.2020.120596.
  110. Omidinia-Anarkoli A, Boesveld S, Tuvshindorj U, Rose JC, Haraszti T, De Laporte L. An Injectable Hybrid Hydrogel with Oriented Short Fibers Induces Unidirectional Growth of Functional Nerve Cells. Small. 2017; 13(36) doi:10.1002/smll.201702207.
  111. Agarwal G, Roy A, Kumar H, Srivastava A. Graphene-collagen cryogel controls neuroinflammation and fosters accelerated axonal regeneration in spinal cord injury. Biomater Adv. 2022; 139:212971. doi:10.1016/j.bioadv.2022.212971.
  112. Zhang L, Li Z, Mao L, Wang H. Circular RNA in Acute Central Nervous System Injuries: A New Target for Therapeutic Intervention. Front Mol Neurosci. 2022; 15:816182. doi:10.3389/fnmol.2022.816182.
  113. Yari D, Ebrahimzadeh MH, Movaffagh J, et al. Biochemical Aspects of Scaffolds for Cartilage Tissue Engineering; from Basic Science to Regenerative Medicine. Arch Bone Jt Surg. 2022; 10(3):229-244. doi:10.22038/ABJS.2022.55549.2766.
  114. Liu X, Hao M, Chen Z, et al. 3D bioprinted neural tissue constructs for spinal cord injury repair. Biomaterials. 2021; 272:120771. doi:10.1016/j.biomaterials.2021.120771.
  115. Yuan TY, Zhang J, Yu T, Wu JP, Liu QY. 3D Bioprinting for Spinal Cord Injury Repair. Front Bioeng Biotechnol. 2022; 10:847344. doi:10.3389/fbioe.2022.847344.
  116. Bedir T, Ulag S, Ustundag CB, Gunduz O. 3D bioprinting applications in neural tissue engineering for spinal cord injury repair. Mater Sci Eng C Mater Biol Appl. 2020; 110:110741. doi:10.1016/j.msec.2020.110741.
  117. Yu X, Zhang T, Li Y. 3D Printing and Bioprinting Nerve Conduits for Neural Tissue Engineering. Polymers (Basel). 2020; 12(8) doi: 10.3390/polym12081637.
  118. Li JJ, Liu H, Zhu Y, et al. Animal Models for Treating Spinal Cord Injury Using Biomaterials-Based Tissue Engineering Strategies. Tissue Eng Part B Rev. 2022; 28(1):79-100. doi:10.1089/ten.TEB.2020.0267.
  119. Choi EH, Gattas S, Brown NJ, et al. Epidural electrical stimulation for spinal cord injury. Neural Regen Res. 2021; 16(12):2367-2375. doi:10.4103/1673-5374.313017.
  120. Golhasani-Keshtan F, Ebrahimzadeh MH, Fattahi AS, Soltani-Moghaddas SH, Omidi-kashani F. Validation and cross-cultural adaptation of the Persian version of Craig Handicap Assessment and Reporting Technique (CHART) short form. Disabil Rehabil. 2013; 35(22):1909-14. doi:10.3109/09638288.2013.768710.
  121. Rajabi-Mashhadi MT, Mashhadinejad H, Ebrahimzadeh MH, Golhasani-Keshtan F, Ebrahimi H, Zarei Z. The Zarit Caregiver Burden Interview Short Form (ZBI-12) in spouses of Veterans with Chronic Spinal Cord Injury, Validity and Reliability of the Persian Version. Arch Bone Jt Surg. 2015; 3(1):56-63.
  122. Melrose J, Hayes AJ, Bix G. The CNS/PNS Extracellular Matrix Provides Instructive Guidance Cues to Neural Cells and Neuroregulatory Proteins in Neural Development and Repair. Int J Mol Sci. 2021; 22(11) doi: 10.3390/ijms22115583.
  123. Kosuri S, Borca CH, Mugnier H, et al. Machine-Assisted Discovery of Chondroitinase ABC Complexes toward Sustained Neural Regeneration. Adv Healthc Mater. 2022; 11(10):e2102101. doi:10.1002/adhm.202102101.
  124. Hayes AJ, Melrose J. Aggrecan, the Primary Weight-Bearing Cartilage Proteoglycan, Has Context-Dependent, Cell-Directive Properties in Embryonic Development and Neurogenesis: Aggrecan Glycan Side Chain Modifications Convey Interactive Biodiversity. Biomolecules. 2020; 10(9). doi:10.3390/biom10091244.
  125. Muir E, De Winter F, Verhaagen J, Fawcett J. Recent advances in the therapeutic uses of chondroitinase ABC. Exp Neurol. 2019; 321:113032. doi:10.1016/j.expneurol.2019.113032.
  126. Jevans B, James ND, Burnside E, et al. Combined treatment with enteric neural stem cells and chondroitinase ABC reduces spinal cord lesion pathology. Stem Cell Res Ther. 2021; 12(1):10. doi:10.1186/s13287-020-02031-9.
  127. Woods W, Evans D, Mogas Barcons A, Tzerakis N, Adams C, Maitreyi Chari D. Stem cell sprays for neurological injuries: a perspective. Emerg Top Life Sci. 2021 Oct 29; 5(4):519-522.doi:10.1042/ETLS20210113.
  128. Azimifar MA, Salmasi Z, Doosti A, Babaei N, Hashemi M. Evaluation of the efficiency of modified PAMAM dendrimer with low molecular weight protamine peptide to deliver IL-12 plasmid into stem cells as cancer therapy vehicles. Biotechnol Prog. 2021; 37(4):e3175. doi:10.1002/btpr.3175.
  129. Lee HL, Yeum CE, Lee H, et al. Peripheral Nerve-Derived Stem Cell Spheroids Induce Functional Recovery and Repair after Spinal Cord Injury in Rodents. Int J Mol Sci. 2021; 22(8) doi: 10.3390/ijms22084141.
  130. Marinval N, Chew SY. Mechanotransduction assays for neural regeneration strategies: A focus on glial cells. APL Bioeng. 2021; 5(2):021505. doi:10.1063/5.0037814.
  131. Pașca SP, Arlotta P, Bateup HS, et al. A nomenclature consensus for nervous system organoids and assembloids. Nature. 2022; 609(7929):907-910. doi:10.1038/s41586-022-05219-6.
  132. Fan B, Wei Z, Feng S. Progression in translational research on spinal cord injury based on microenvironment imbalance. Bone Res. 2022; 10(1):35. doi:10.1038/s41413-022-00199-9.
  133. Awad BI, Carmody MA, Steinmetz MP. Potential role of growth factors in the management of spinal cord injury. World Neurosurg. 2015; 83(1):120-31. doi:10.1016/j.wneu.2013.01.042.
  134. Talifu Z, Qin C, Xin Z, et al. The Overexpression of Insulin-Like Growth Factor-1 and Neurotrophin-3 Promote Functional Recovery and Alleviate Spasticity after Spinal Cord Injury. Front Neurosci. 2022; 16:863793. doi:10.3389/fnins.2022.863793.
  135. Cooke P, Janowitz H, Dougherty SE. Neuronal Redevelopment and the Regeneration of Neuromodulatory Axons in the Adult Mammalian Central Nervous System. Front Cell Neurosci. 2022; 16:872501. doi:10.3389/fncel.2022.872501.
  136. Gu Y, Wen G, Zhao H, Qi H, Yang Y, Hu T. Delivery of FGF10 by implantable porous gelatin microspheres for treatment of spinal cord injury. Mol Med Rep. 2023; 28(1) doi:10.3892/mmr.2023.13024.
  137. Moshiri M, Hosseiniyan SM, Moallem SA, et al. The effects of vitamin B (12) on the brain damages caused by methamphetamine in mice. Iran J Basic Med Sci. 2018; 21(4):434-438. doi:10.22038/IJBMS.2018.23362.5897.
  138. Aschauer-Wallner S, Leis S, Bogdahn U, Johannesen S, Couillard-Despres S, Aigner L. Granulocyte colony-stimulating factor in traumatic spinal cord injury. Drug Discov Today. 2021; 26(7):1642-1655. doi:10.1016/j.drudis.2021.03.014.
  139. Derakhshanrad N, Saberi H, Yekaninejad MS, Joghataei MT, Sheikhrezaei A. Granulocyte-colony stimulating factor administration for neurological improvement in patients with postrehabilitation chronic incomplete traumatic spinal cord injuries: a double-blind randomized controlled clinical trial. J Neurosurg Spine. 2018; 29(1):97-107. doi:10.3171/2017.11.SPINE17769.
  140. Pelisch N, Rosas Almanza J, Stehlik KE, Aperi BV, Kroner A. CCL3 contributes to secondary damage after spinal cord injury. J Neuroinflammation. 2020; 17(1):362. doi:10.1186/s12974-020-02037-3.
  141. Kim HN, McCrea MR, Li S. Advances in molecular therapies for targeting pathophysiology in spinal cord injury. Expert Opin Ther Targets. 2023; 27(3):171-187. doi:10.1080/14728222.2023.2194532.
  142. Ding Y, Chen Q. mTOR pathway: A potential therapeutic target for spinal cord injury. Biomed Pharmacother. 2022; 145:112430. doi:10.1016/j.biopha.2021.112430.
  143. Wang W, He D, Chen J, et al. Circular RNA Plek promotes fibrogenic activation by regulating the miR-135b-5p/TGF-betaR1 axis after spinal cord injury. Aging (Albany NY). 2021; 13(9):13211-13224. doi:10.18632/aging.203002.
  144. Hu M, Cao Z, Jiang D. The Effect of miRNA-Modified Exosomes in Animal Models of Spinal Cord Injury: A meta-Analysis. Front Bioeng Biotechnol. 2021; 9:819651. doi:10.3389/fbioe.2021.819651.
  145. Shen Y, Cai J. The Importance of Using Exosome-Loaded miRNA for the Treatment of Spinal Cord Injury. Mol Neurobiol. 2023; 60(2):447-459. doi:10.1007/s12035-022-03088-8.
  146. Liu XY, Guo JW, Kou JQ, Sun YL, Zheng XJ. Repair mechanism of astrocytes and non-astrocytes in spinal cord injury. World J Clin Cases. 2020; 8(5):854-863. doi:10.12998/wjcc.v8.i5.854.
  147. Tran AP, Warren PM, Silver J. New insights into glial scar formation after spinal cord injury. Cell Tissue Res. 2022; 387(3):319-336. doi:10.1007/s00441-021-03477-w.
  148. Costachescu B, Niculescu AG, Dabija MG, Teleanu RI, Grumezescu AM, Eva L. Novel Strategies for Spinal Cord Regeneration. Int J Mol Sci. 2022; 23(9) doi: 10.3390/ijms23094552.
  149. Bao T, Li N, Chen H, et al. Drug-Loaded Zwitterion-Based Nanomotors for the Treatment of Spinal Cord Injury. ACS Appl Mater Interfaces. 2023; 15(27):32762-32771. doi:10.1021/acsami.3c05866.
  150. Behroozi Z, Rahimi B, Hamblin MR, Nasirinezhad F, Janzadeh A, Ramezani F. Injection of Cerium Oxide Nanoparticles to Treat Spinal Cord Injury in Rats. J Neuropathol Exp Neurol. 2022;doi:10.1093/jnen/nlac026.
  151. Murphy C, Thomas FP. Generative AI in spinal cord injury research and care: Opportunities and challenges ahead. J Spinal Cord Med. 2023; 46(3):341-342. doi:10.1080/10790268.2023.2198926.
  152. Khan O, Badhiwala JH, Grasso G, Fehlings MG. Use of Machine Learning and Artificial Intelligence to Drive Personalized Medicine Approaches for Spine Care. World Neurosurg. 2020; 140:512-518. doi:10.1016/j.wneu.2020.04.022.
  153. Marrotte EJ, Johnson K, Schweller RM, et al. Induction of Neurogenesis and Angiogenesis in a Rat Hemisection Spinal Cord Injury Model With Combined Neural Stem Cell, Endothelial Progenitor Cell, and Biomimetic Hydrogel Matrix Therapy. Crit Care Explor. 2021; 3(6):e0436. doi:10.1097/CCE.0000000000000436.
  154. Ebrahimian M, Hashemi M, Etemad L, Salmasi Z. Thymoquinone-loaded mesenchymal stem cell-derived exosome as an efficient nano-system against breast cancer cells. Iran J Basic Med Sci. 2022; 25(6):723-731. doi:10.22038/IJBMS.2022.64092.14116.
  155. Fan L, Liu C, Chen X, et al. Exosomes-Loaded Electroconductive Hydrogel Synergistically Promotes Tissue Repair after Spinal Cord Injury via Immunoregulation and Enhancement of Myelinated Axon Growth. Adv Sci (Weinh). 2022; 9(13):e2105586. doi:10.1002/advs.202105586.
  156. Senger JB, Chan AWM, Chan KM, et al. Conditioning Electrical Stimulation Is Superior to Postoperative Electrical Stimulation in Enhanced Regeneration and Functional Recovery Following Nerve Graft Repair. Neurorehabil Neural Repair. 2020; 34(4):299-308. doi:10.1177/1545968320905801.
  157. Fadeev FO, Bashirov FV, Markosyan VA, et al. Combination of epidural electrical stimulation with ex vivo triple gene therapy for spinal cord injury: a proof of principle study. Neural Regen Res. 2021; 16(3):550-560. doi:10.4103/1673-5374.293150.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

  1. Zheng Y, Mao YR, Yuan TF, Xu DS, Cheng LM. Multimodal treatment for spinal cord injury: a sword of neuroregeneration upon neuromodulation. Neural Regen Res. 2020; 15(8):1437-1450. doi:10.4103/1673-5374.274332.
  2. Griffin JM, Bradke F. Therapeutic repair for spinal cord injury: combinatory approaches to address a multifaceted problem. EMBO Mol Med. 2020; 12(3):e11505. doi:10.15252/emmm.201911505.
  3. Khaing ZZ, Chen JY, Safarians G, et al. Clinical Trials Targeting Secondary Damage after Traumatic Spinal Cord Injury. Int J Mol Sci. 2023; 24(4) doi: 10.3390/ijms24043824.
The Archives of Bone and Joint Surgery
Volume 12, Issue 6
June 2024
Pages 380-399

  • Receive Date 24 July 2023
  • Revise Date 25 April 2024
  • Accept Date 07 October 2023