Concise review: Bridging the gap: Novel neuroregenerative and neuroprotective strategies in spinal cord injury

Stem Cells Translational Medicine

Volumn 5, Issue 7, 2016, Pages 914-924

  Ahuja, Christopher S ^a,b   Fehlings, Michael ^a,b,c,d  

^a Department of Surgery   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

^c UNIVERSITY HEALTH NETWORK   (Canada)

^d UNIVERSITY OF TORONTO   (Canada)

Author keywords

Biomaterial; Neuroprotection; Neuroregeneration; Spinal cord injury; Stem cell; Trauma

Indexed keywords

BASIC FIBROBLAST GROWTH FACTOR RECEPTOR; METHYLPREDNISOLONE; MINOCYCLINE; PLACEBO; RILUZOLE; SUN 13837; UNCLASSIFIED DRUG; VX 210; ANTIINFLAMMATORY AGENT; NEUROPROTECTIVE AGENT; SODIUM CHANNEL BLOCKING AGENT;

BLOOD PRESSURE MONITORING; CELL INFILTRATION; CELL SURVIVAL; EXCITOTOXICITY; HUMAN; HYPOTHERMIA; INJURY SEVERITY; MUTAGENESIS; NERVE FIBER REGENERATION; NERVE REGENERATION; NEUROPROTECTION; OLIGODENDROGLIA; PLURIPOTENT STEM CELL; REVIEW; SPINAL CORD INJURY; ANIMAL; CLINICAL TRIAL (TOPIC); DECOMPRESSION SURGERY; DRUG EFFECTS; GLIA; INDUCED HYPOTHERMIA; PATHOPHYSIOLOGY; PHYSIOLOGY; SPINAL CORD INJURIES;

ANIMALS; ANTI-INFLAMMATORY AGENTS; CLINICAL TRIALS AS TOPIC; DECOMPRESSION, SURGICAL; HUMANS; HYPOTHERMIA, INDUCED; NERVE REGENERATION; NEUROGLIA; NEUROPROTECTION; NEUROPROTECTIVE AGENTS; SODIUM CHANNEL BLOCKERS; SPINAL CORD INJURIES;

EID: 84976448364     PISSN: 21576564     EISSN: 21576580     Source Type: Journal    
DOI: 10.5966/sctm.2015-0381     Document Type: Review

References (150)

1. Spinal cord injury facts and figures at a glance. J Spinal Cord Med 2014; 37: 117–118.
2. Christopher and Dana Reeve Foundation. One degree of separation: Paralysis and spinal cord injury in the United States. 2010. Available at http: //www.christopherreeve. org/site/c.ddJFKRNo Fi G/b. 5091685/k. 58BD/ One_Degree_of_Separation. htm. Accessed March 31, 2016.
3. La Placa MC, Simon CM, Prado GR et al. CNS injury biomechanics and experimental models. Prog Brain Res 2007; 161: 13–26.
4. Choo AM, Liu J, Lam CK et al. Contusion, dislocation, and distraction: Primary hemorrhage and membrane permeability in distinct mechanisms of spinal cord injury. J Neurosurg Spine 2007; 6: 255–266.
5. Whetstone WD, Hsu JY, Eisenberg M et al. Blood-spinal cord barrier after spinal cord injury: Relation to revascularization and wound healing. J Neurosci Res 2003; 74: 227–239.
6. Mautes AE, Weinzierl MR, Donovan F et al. Vascular events after spinal cord injury: Contribution to secondary pathogenesis. Phys Ther 2000; 80: 673–687.
7. Waxman SG. Demyelination in spinal cord injury. J Neurol Sci 1989; 91: 1–14.
8. Li S, Mealing GA, Morley P et al. Novel injury mechanism in anoxia and trauma of spinal cord white matter: Glutamate release via reverse Na+-dependent glutamate transport. J Neurosci 1999; 19: RC16.
9. Li S, Stys PK. Mechanisms of ionotropic glutamate receptor-mediated excitotoxicity in isolated spinal cord white matter. J Neurosci 2000; 20: 1190–1198.
10. Guha A, Tator CH, Rochon J. Spinal cord blood flow and systemic blood pressure after experimental spinal cord injury in rats. Stroke 1989; 20: 372–377.
11. Guha A, Tator CH. Acute cardiovascular effects of experimental spinal cord injury. J Trauma 1988; 28: 481–490.
12. Milhorat TH, Capocelli AL Jr, Anzil AP et al. Pathological basis of spinal cord cavitation in syringomyelia: Analysis of 105 autopsy cases. J Neurosurg 1995; 82: 802–812.
13. Yuan YM, He C. The glial scar in spinal cord injury and repair. Neurosci Bull 2013; 29: 421–435.
14. Snow DM, Lemmon V, Carrino DA et al. Sulfated proteoglycans in astroglial barriers inhibit neurite outgrowth in vitro. Exp Neurol 1990; 109: 111–130.
15. Höke A, Silver J. Proteoglycans and other repulsive molecules in glial boundaries during development and regeneration of the nervous system. Prog Brain Res 1996; 108: 149–163.
16. Becker T, Anliker B, Becker CG et al. Tenascin-R inhibits regrowth of optic fibers in vitro and persists in the optic nerve of mice after injury. Glia 2000; 29: 330–346.
17. Silver J. Inhibitory molecules in developmentandregeneration. J Neurol 1994; 242 (suppl 1): S22–S24.
18. Butt AM, Duncan A, Hornby MF et al. Cells expressing the NG2 antigen contact nodes of Ranvier in adult CNS white matter. Glia 1999; 26: 84–91.
19. Jones LL, Yamaguchi Y, Stallcup WB et al. NG2 is a major chondroitin sulfate proteoglycan produced after spinal cord injury and is expressed by macrophages and oligodendrocyte progenitors. J Neurosci 2002; 22: 2792–2803.
20. McKeon RJ, Schreiber RC, Rudge JS et al. Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. J Neurosci 1991; 11: 3398–3411.
21. Forgione N, Fehlings MG. Rho-ROCK inhibition in the treatment of spinal cord injury. World Neurosurg 2014; 82: e535–e539.
22. Chen MS, Huber AB, van der Haar ME et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 2000; 403: 434–439.
23. Moreau-Fauvarque C, Kumanogoh A, Camand E et al. The transmembrane semaphorin Sema4D/CD100, an inhibitor of axonal growth, is expressed on oligodendrocytes and upregulated after CNS lesion. J Neurosci 2003; 23: 9229–9239.
24. Cafferty WB, Duffy P, Huebner E et al. MAG and OMgp synergize with Nogo-A to restrict axonal growth and neurological recovery after spinal cord trauma. J Neurosci 2010; 30: 6825–6837.
25. Nashmi R, Fehlings MG. Mechanisms of axonal dysfunction after spinal cord injury: With an emphasis on the role of voltage-gated potassium channels. Brain Res Brain Res Rev 2001; 38: 165–191.
26. Nashmi R, Fehlings MG. Changes in axonal physiology and morphology after chronic compressive injury of the rat thoracic spinal cord. Neuroscience 2001; 104: 235–251.
27. Bhatt JM, Gordon PH. Current clinical trials in amyotrophic lateral sclerosis. Expert Opin Investig Drugs 2007; 16: 1197–1207.
28. Azbill RD, Mu X, Springer JE. Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes. Brain Res 2000; 871: 175–180.
29. Nógrádi A, Szabó A, Pintér S et al. Delayed riluzole treatment is able to rescue injuredrat spinalmotoneurons. Neuroscience 2007; 144: 431–438.
30. Stutzmann JM, Pratt J, Boraud T et al. The effect of riluzole on post-traumatic spinal cord injury in the rat. Neuroreport 1996; 7: 387–392.
31. Fehlings MG, Wilson JR, Frankowski RF et al. Riluzole for the treatment of acute traumatic spinal cord injury: Rationale for and design of the NACTN Phase I clinical trial. J Neurosurg Spine 2012; 17 (1 suppl): 151–156.
32. Wells JE, Hurlbert RJ, Fehlings MG et al. Neuroprotection by minocycline facilitates significant recovery from spinal cord injury in mice. Brain 2003; 126: 1628–1637.
33. Casha S, Zygun D, McGowan MD et al. Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain 2012; 135: 1224–1236.
34. Minocycline in acute spinal cord injury (MASC), NCT identifier: NCT01828203. Available at https://clinicaltrials.gov/ct2/show/NCT01828203?term=NCT01828203&rank=1. Accessed July 21, 2015.
35. Fehlings MG, Wilson JR, Cho N. Methylprednisolone for the treatment of acute spinal cord injury: counterpoint. Neurosurgery 2014; 61 (suppl 1): 36–42.
36. Bracken MB, Collins WF, Freeman DF et al. Efficacy of methylprednisolone in acute spinal cord injury. JAMA 1984; 251: 45–52.
37. Bracken MB, Shepard MJ, Collins WF et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 1990; 322: 1405–1411.
38. Bracken MB, Shepard MJ, Holford TR et al. Administration of methylprednisolone for 24 or 48 hours or tirilazadmesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA 1997; 277: 1597–1604.
39. Guyatt GH, Oxman AD, Kunz R et al. Going from evidence to recommendations. BMJ 2008; 336: 1049–1051.
40. Guyatt GH, Oxman AD, Kunz R et al. Incorporatingconsiderationsof resourcesuseinto grading recommendations. BMJ 2008; 336: 1170–1173.
41. Guyatt GH, Oxman AD, Kunz R et al. What is “quality of evidence” and why is it important to clinicians? BMJ 2008; 336: 995–998.
42. Guyatt GH, Oxman AD, Vist GE et al. GRADE: An emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336: 924–926.
43. Jaeschke R, Guyatt GH, Dellinger P et al. Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive. BMJ 2008; 337: a744.
44. Schünemann HJ, Oxman AD, Brozek J et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ 2008; 336: 1106–1110.
45. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346: 549–556.
46. Papile LA, Baley JE, Benitz W et al. Hypothermia and neonatal encephalopathy. Pediatrics 2014; 133: 1146–1150.
47. Kwon BK, Mann C, Sohn HM et al. Hypothermia for spinal cord injury. Spine J 2008; 8: 859–874.
48. Levi AD, Green BA, Wang MY et al. Clinical application of modest hypothermia after spinal cord injury. J Neurotrauma 2009; 26: 407–415.
49. The Miami Project to Cure Paralysis. Neuroprotection—therapeutic hypothermia. 2014. Available at http: //www. themiamiproject. org/ research/what-are-clinical-trials/clinical-trials/ therapeutic-hypothermia-acute/. Accessed October 15, 2015.
50. Fehlings MG, Vaccaro A, Wilson JR et al. Early versus delayed decompression for traumatic cervical spinal cord injury: Results of the Surgical Timing in Acute Spinal Cord Injury Study (STASCIS). PLo S One 2012; 7: e32037.
51. Wilson JR, Singh A, Craven C et al. Early versus late surgery for traumatic spinal cord injury: Rhe results of a prospective Canadian cohort study. Spinal Cord 2012; 50: 840–843.
52. Dvorak MFNV, Noonan VK, Fallah N et al. The influence of time from injury to surgery on motor recovery and length of hospital stay in acute traumatic spinal cord injury: an observational Canadian cohort study. J Neurotrauma 2015; 32: 645–654.
53. Wallner S, Peters S, Pitzer C et al. The granulocyte-colony stimulating factor has a dual role in neuronal and vascular plasticity. Front Cell Dev Biol 2015; 3: 48.
54. Nishio Y, Koda M, Kamada T et al. Granulocyte colony-stimulating factor attenuates neuronal death and promotes functional recovery after spinal cord injury inmice. J Neuropathol Exp Neurol 2007; 66: 724–731.
55. Takahashi H, Yamazaki M, Okawa A 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: 2580–2587.
56. Kamiya K, Koda M, Furuya T et al. Neuroprotective therapy with granulocyte colonystimulating factor in acute spinal cord injury: A comparisonwith high-dosemethylprednisolone as a historical control. Eur Spine J 2015; 24: 963–967.
57. Wilson JR, Forgione N, Fehlings MG. Emerging therapies for acute traumatic spinal cord injury. CMAJ 2013; 185: 485–492.
58. Resnick DK. Updated guidelines for the management of acute cervical spine and spinal cord injury. Neurosurgery 2013; 72 (suppl 2): 1.
59. Kaptanoglu E, Beskonakli E, Solaroglu I et al. Magnesium sulfate treatment in experimental spinal cord injury: Emphasis on vascular changes and early clinical results. Neurosurg Rev 2003; 26: 283–287.
60. Siddiqui AM, Khazaei M, Fehlings MG. Translatingmechanisms of neuroprotection, regeneration, and repair to treatment of spinal cord injury. Prog Brain Res 2015; 218: 15–54.
61. Bradbury EJ, Moon LDF, Popat RJ et al. Chondroitinase ABCpromotes functional recovery after spinal cord injury. Nature 2002; 416: 636–640.
62. Jones LL, Sajed D, Tuszynski MH. Axonal regeneration through regions of chondroitin sulfate proteoglycan deposition after spinal cord injury: A balance of permissiveness and inhibition. J Neurosci 2003; 23: 9276–9288.
63. Ikegami T, Nakamura M, Yamane J et al. Chondroitinase ABC combined with neural stem/progenitor cell transplantation enhances graft cell migration and outgrowth of growthassociated protein-43-positive fibers after rat spinal cord injury. Eur J Neurosci 2005; 22: 3036–3046.
64. Carter LM, McMahon SB, Bradbury EJ. Delayed treatment with chondroitinase ABC reverses chronic atrophy of rubrospinal neurons following spinal cord injury. Exp Neurol 2011; 228: 149–156.
65. Bartus K, James ND, Didangelos A et al. Large-scale chondroitin sulfate proteoglycan digestion with chondroitinase gene therapy leads to reduced pathology andmodulates macrophage phenotypefollowing spinal cordcontusioninjury. J Neurosci 2014; 34: 4822–4836.
66. Niederöst B, Oertle T, Fritsche J et al. Nogo-A and myelin-associated glycoprotein mediate neurite growth inhibition by antagonistic regulation of Rho A and Raci. J Neurosci 2002; 22: 10368–10376.
67. Freund P, Schmidlin E, Wannier T et al. Nogo-A-specific antibody treatment enhances sprouting and functional recovery after cervical lesion in adult primates. Nat Med 2006; 12: 790–792.
68. Gonzenbach RR, Schwab ME. Disinhibition of neurite growth to repair the injured adult CNS: Focusing on Nogo. Cell Mol Life Sci 2008; 65: 161–176.
69. Liebscher T, Schnell L, Schnell D et al. Nogo-A antibody improves regeneration and locomotion of spinal cord-injured rats. Ann Neurol 2005; 58: 706–719.
70. Meininger V, Pradat P-F, Corse A et al. Safety, pharmacokinetic, and functional effects of the Nogo-a monoclonal antibody in amyotrophic lateral sclerosis: A randomized, first-inhuman clinical trial. PLo S One 2014; 9: e97803.
71. Fehlings MG, Theodore N, Harrop J et al. A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury. J Neurotrauma 2011; 28: 787–796.
72. Bai L, Lennon DP, Eaton V et al. Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 2009; 57: 1192–1203.
73. Arriola A, Kiel ME, Shi Y et al. Adjunctive MSCs enhance myelin formation by xenogenic oligodendrocyte precursors transplanted in the retina. Cell Res 2010; 20: 728–731.
74. Zhang J, Wang B, Xiao Z et al. Olfactory ensheathing cells promote proliferation and inhibit neuronal differentiation of neural progenitor cells through activation of Notch signaling. Neuroscience 2008; 153: 406–413.
75. Wang L, Shi J, van Ginkel FW et al. Neural stem/progenitor cellsmodulateimmuneresponses by suppressing T lymphocytes with nitric oxide and prostaglandin E2. Exp Neurol 2009; 216: 177–183.
76. Okamura RM, Lebkowski J, Au M et al. Immunological properties of human embryonic stem cell-derived oligodendrocyte progenitor cells. J Neuroimmunol 2007; 192: 134–144.
77. Jäderstad J, Jäderstad LM, Li J et al. Communication via gap junctions underlies early functional and beneficial interactions between grafted neural stem cells and the host. Proc Natl Acad Sci USA 2010; 107: 5184–5189.
78. Curt ACS, Fehlings M, Huhn S. Phase I/II clinical trial of Hu CNS-SC cells in chronic thoracic spinal cord injury—interim analysis. 2014. http://www.stemcellsinc.com/Presentations/ASIA_FINAL.pdf. Accessed October 15, 2015.
79. Hawryluk GW, Fehlings MG. The center of the spinal cord may be central to its repair. Cell Stem Cell 2008; 3: 230–232.
80. Martens DJ, Seaberg RM, van der Kooy D. In vivo infusions of exogenous growth factors into the fourth ventricle of the adult mouse brain increase the proliferation of neural progenitors around the fourth ventricle and the central canal of the spinal cord. Eur J Neurosci 2002; 16: 1045–1057.
81. Espinosa-Jeffrey A, Oregel K, Wiggins L et al. Strategies for endogenous spinal cord repair: HPMA hydrogel to recruit migrating endogenous stem cells. Adv Exp Med Biol 2012; 760: 25–52.
82. Babona-Pilipos R, Popovic MR, Morshead CM. A galvanotaxis assay for analysis of neural precursor cell migration kinetics in an externally applied direct current electric field. J Vis Exp 2012.
83. Draper JS, Moore HD, Ruban LN et al. Culture and characterization of human embryonic stem cells. Stem Cells Dev 2004; 13: 325–336.
84. Draper JS, Smith K, Gokhale P et al. Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells. Nat Biotechnol 2004; 22: 53–54.
85. Brambrink T, Foreman R, Welstead GG et al. Sequential expression of pluripotency markers during direct reprogramming of mouse somatic cells. Cell Stem Cell 2008; 2: 151–159.
86. Stadtfeld M, Nagaya M, Utikal J et al. Induced pluripotent stem cells generated without viral integration. Science 2008; 322: 945–949.
87. Woltjen K, Michael IP, Mohseni P et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 2009; 458: 766–770.
88. Salewski RP, Eftekharpour E, Fehlings MG. Are induced pluripotent stem cells the future of cell-based regenerative therapies for spinal cord injury? J Cell Physiol 2010; 222: 515–521.
89. Hu BY, Weick JP, Yu J et al. Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc Natl Acad Sci USA 2010; 107: 4335–4340.
90. Feng Q, Lu S-J, Klimanskaya I et al. Hemangioblastic derivatives from human induced pluripotent stem cells exhibit limited expansion and early senescence. STEM CELLS 2010; 28: 704–712.
91. Vaskova EA, Stekleneva AE, Medvedev SP et al. “Epigenetic memory” phenomenon in induced pluripotent stem cells. Acta Naturae 2013; 5: 15–21.
92. Dasari VR, Veeravalli KK, Dinh DH. Mesenchymal stem cells in the treatment of spinal cord injuries: A review. World J Stem Cells 2014; 6: 120–133.
93. Swartzlander MD, Blakney AK, Amer LD et al. Immunomodulation by mesenchymal stem cells combats the foreign body response to cell-laden synthetic hydrogels. Biomaterials 2015; 41: 79–88.
94. Bessout R, Sémont A, Demarquay C et al. Mesenchymal stem cell therapy induces glucocorticoid synthesis in colonic mucosa and suppresses radiation-activated T cells: New insights into MSC immunomodulation. Mucosal Immunol 2014; 7: 656–669.
95. Lim JH, Kim JS, Yoon IH et al. Immunomodulation of delayed-type hypersensitivity responses bymesenchymal stemcells is associated with bystander T cell apoptosis in the draining lymph node. J Immunol 2010; 185: 4022–4029.
96. Quertainmont R, Cantinieaux D, Botman O et al. Mesenchymal stem cell graft improves recovery after spinal cord injury in adult rats through neurotrophic and pro-angiogenic actions. PLo S One 2012; 7: e39500.
97. Kim JW, Ha KY, Molon JN et al. Bone marrow-derived mesenchymal stem cell transplantation for chronic spinal cord injury in rats: comparative study between intralesional and intravenous transplantation. Spine 2013; 38: E1065–E1074.
98. Jarocha D, Milczarek O, Kawecki Z et al. Preliminary study of autologous bone marrow nucleated cells transplantation in children with spinal cord injury. STEM CELLS TRANSLATIONAL MEDICINE 2014; 3: 395–404.
99. Windus LC, Lineburg KE, Scott SE et al. Lamellipodia mediate the heterogeneity of central olfactory ensheathing cell interactions. Cell Mol Life Sci 2010; 67: 1735–1750.
100. Silva NA, Cooke MJ, Tam RY et al. The effects of peptide modified gellan gum and olfactory ensheathing glia cells on neural stem/progenitor cell fate. Biomaterials 2012; 33: 6345–6354.
101. Liu J, Chen P, Wang Q et al. Meta analysis of olfactory ensheathing cell transplantation promoting functional recovery of motor nerves in rats with complete spinal cord transection. Neural Regen Res 2014; 9: 1850–1858.
102. Li L, Adnan H, Xu B et al. Effects of transplantation of olfactory ensheathing cells in chronic spinal cord injury: A systematic review and meta-analysis. Eur Spine J 2015; 24: 919–930.
103. Nistor GI, Totoiu MO, Haque N et al. Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia 2005; 49: 385–396.
104. Tetzlaff W, Okon EB, Karimi-Abdolrezaee S et al. A systematic review of cellular transplantation therapies for spinal cord injury. J Neurotrauma 2011; 28: 1611–1682.
105. Gil J-E, Woo D-H, Shim J-H et al. Vitronectin promotes oligodendrocyte differentiation during neurogenesis of human embryonic stem cells. FEBS Lett 2009; 583: 561–567.
106. Lu P, Woodruff G, Wang Y et al. Longdistance axonal growth from human induced pluripotent stem cells after spinal cord injury. Neuron 2014; 83: 789–796.
107. Bregman BS, Kunkel-Bagden E, Reier PJ et al. Recovery of function after spinal cord injury: mechanisms underlying transplantmediated recovery of function differ after spinal cord injury in newborn and adult rats. Exp Neurol 1993; 123: 3–16.
108. Jakeman LB, Reier PJ. Axonal projections between fetal spinal cord transplants and the adult rat spinal cord: A neuroanatomical tracing study of local interactions. J Comp Neurol 1991; 307: 311–334.
109. Torper O, Pfisterer U, Wolf DA et al. Generation of induced neurons via direct conversion in vivo. Proc Natl Acad Sci USA 2013; 110: 7038–7043.
110. Hu B-Y, Zhang S-C. Differentiation of spinal motor neurons from pluripotent human stem cells. Nat Protoc 2009; 4: 1295–1304.
111. Raper J, Mason C. Cellular strategies of axonal pathfinding. Cold Spring Harb Perspect Biol 2010; 2: a001933.
112. van den Pol AN, Kim WT. NILE/L1 and NCAM-polysialic acid expression on growing axons of isolated neurons. J Comp Neurol 1993; 332: 237–257.
113. Zhang S, Xia YY, Lim HC et al. NCAMmediated locomotor recovery from spinal cord contusion injury involves neuroprotection, axon regeneration, and synaptogenesis. Neurochem Int 2010; 56: 919–929.
114. Wolman MA, Sittaramane VK, Essner JJ et al. Transient axonal glycoprotein-1 (TAG-1) and laminin-alpha1 regulate dynamic growth cone behaviors and initial axon direction in vivo. Neural Dev 2008; 3: 6.
115. Blackmore M, Letourneau PC. L1, beta1 integrin, and cadherins mediate axonal regeneration in the embryonic spinal cord. J Neurobiol 2006; 66: 1564–1583.
116. Zhang L, Kaneko S, Kikuchi K et al. Rewiring of regenerated axons by combining treadmill training with semaphorin3A inhibition. Mol Brain 2014; 7: 14.
117. Kennedy TE, Wang H, Marshall W et al. Axon guidance by diffusible chemoattractants: A gradient of netrin protein in the developing spinal cord. J Neurosci 2006; 26: 8866–8874.
118. Karimi-Abdolrezaee S, Eftekharpour E, Wang J et al. Delayed transplantation of adult neural precursor cells promotes remyelination and functional neurological recovery after spinal cord injury. J Neurosci 2006; 26: 3377–3389.
119. Karimi-Abdolrezaee S, Eftekharpour E, Wang J et al. Synergistic effects of transplanted adult neural stem/progenitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord. J Neurosci 2010; 30: 1657–1676.
120. Liu WG, Wang ZY, Huang ZS. Bone marrow-derived mesenchymal stem cells expressing the bFGF transgene promote axon regeneration and functional recovery after spinal cord injury in rats. Neurol Res 2011; 33: 686–693.
121. Jeong SR, Kwon MJ, Lee HG et al. Hepatocyte growth factor reduces astrocytic scar formation and promotes axonal growth beyond glial scars after spinal cord injury. Exp Neurol 2012; 233: 312–322.
122. Tobias CA, Shumsky JS, Shibata M et al. Delayed grafting of BDNF and NT-3 producing fibroblasts into the injured spinal cord stimulates sprouting, partially rescues axotomized red nucleus neurons from loss and atrophy, and provides limited regeneration. Exp Neurol 2003; 184: 97–113.
123. Zhang YJ, Zhang W, Lin CG et al. Neurotrophin-3 gene modified mesenchymal stem cells promote remyelination and functional recovery in the demyelinated spinal cord of rats. J Neurol Sci 2012; 313: 64–74.
124. Sasaki M, Radtke C, Tan AM et al. BDNF-hypersecreting human mesenchymal stemcells promote functional recovery, axonal sprouting, and protection of corticospinal neurons after spinal cord injury. J Neurosci 2009; 29: 14932–14941.
125. Blesch A, Tuszynski MH. Cellular GDNF delivery promotes growth of motor and dorsal column sensory axons after partial and complete spinal cord transections and induces remyelination. J Comp Neurol 2003; 467: 403–417.
126. Rooney GE, McMahon SS, Ritter T et al. Neurotrophic factor-expressing mesenchymal stem cells survive transplantation into the contused spinal cord without differentiating into neural cells. Tissue Eng Part A 2009; 15: 3049–3059.
127. Vulic K, Shoichet MS. Tunable growth factor delivery from injectable hydrogels for tissue engineering. J Am Chem Soc 2012; 134: 882–885.
128. Mayfield AE, Tilokee EL, Latham N et al. The effect of encapsulation of cardiac stem cells withinmatrix-enriched hydrogel capsules on cell survival, post-ischemic cell retention and cardiac function. Biomaterials 2014; 35: 133–142.
129. Lippens E, Swennen I, Gironès J et al. Cell survival and proliferation after encapsulation in a chemically modified Pluronic (R) F127 hydrogel. J Biomater Appl 2013; 27: 828–839.
130. Hwang DH, Shin HY, Kwon MJ et al. Survival of neural stem cell grafts in the lesioned spinal cord is enhanced by a combination of treadmill locomotor training via insulin-like growth factor-1 signaling. J Neurosci 2014; 34: 12788–12800.
131. Gupta D, Tator CH, Shoichet MS. Fastgelling injectable blend of hyaluronan and methylcellulose for intrathecal, localized delivery to the injured spinal cord. Biomaterials 2006; 27: 2370–2379.
132. Itosaka H, Kuroda S, Shichinohe H 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: 248–257.
133. Teng YD, Lavik EB, Qu X et al. Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc Natl Acad Sci USA 2002; 99: 3024–3029.
134. Stokols S, Tuszynski MH. Freeze-dried agarose scaffolds with uniaxial channels stimulate and guide linear axonal growth following spinal cord injury. Biomaterials 2006; 27: 443–451.
135. Gros T, Sakamoto JS, Blesch A et al. Regeneration of long-tract axons through sites of spinal cord injury using templated agarose scaffolds. Biomaterials 2010; 31: 6719–6729.
136. Tsai EC, Dalton PD, Shoichet MS et al. Matrix inclusion within synthetic hydrogel guidance channels improves specific supraspinal and local axonal regeneration after complete spinal cord transection. Biomaterials 2006; 27: 519–533.
137. Mothe AJ, Tam RY, Zahir T et al. Repair of the injured spinal cord by transplantation of neural stem cells in a hyaluronan-based hydrogel. Biomaterials 2013; 34: 3775–3783.
138. Taylor SJ, McDonald JW 3rd, Sakiyama-Elbert SE. Controlled release of neurotrophin-3 from fibrin gels for spinal cord injury. J Control Release 2004; 98: 281–294.
139. Ansorena E, De Berdt P, Ucakar B et al. Injectable alginate hydrogel loaded with GDNF promotes functional recovery in a hemisection model of spinal cord injury. Int J Pharm 2013; 455: 148–158.
140. Shen YH, Shoichet MS, Radisic M. Vascular endothelial growth factor immobilized in collagen scaffold promotes penetration and proliferation of endothelial cells. Acta Biomater 2008; 4: 477–489.
141. Leipzig ND, Xu C, Zahir T et al. Functional immobilization of interferon-gamma induces neuronal differentiation of neural stem cells. J Biomed Mater Res A 2010; 93: 625–633.
142. Jain A, Kim YT, McKeon RJ et al. In situ gelling hydrogels for conformal repair of spinal cord defects, and local delivery of BDNF after spinal cord injury. Biomaterials 2006; 27: 497–504.
143. Taylor SJ, Rosenzweig ES, McDonald JW 3rd, Sakiyama-Elbert SE. Delivery of neurotrophin-3 from fibrin enhances neuronal fiber sprouting after spinal cord injury. J Control Release 2006; 113: 226–235.
144. Caplan MR, Schwartzfarb EM, Zhang S et al. Effects of systematic variation of amino acid sequence on the mechanical properties of a self-assembling, oligopeptide biomaterial. J Biomater Sci Polym Ed 2002; 13: 225–236.
145. Segers VF, Lee RT. Local delivery of proteins and the use of self-assembling peptides. Drug Discov Today 2007; 12: 561–568.
146. Liu Y, Ye H, Satkunendrarajah K et al. A self-assembling peptide reduces glial scarring, attenuates post-traumatic inflammation and promotes neurological recovery following spinal cord injury. Acta Biomater 2013; 9: 8075–8088.
147. Tysseling-Mattiace VM, Sahni V, Niece KL et al. Self-assembling nanofibers inhibit glial scar formationandpromoteaxonelongation after spinal cord injury. J Neurosci 2008; 28: 3814–3823.
148. Iwasaki M, Wilcox JT, Nishimura Y et al. Synergistic effects of self-assembling peptide and neural stem/progenitor cells to promote tissue repair and forelimb functional recovery in cervical spinal cord injury. Biomaterials 2014; 35: 2617–2629.
149. Cadotte DW, Fehlings MG. Will imaging biomarkers transform spinal cord injury trials? Lancet Neurol 2013; 12: 843–844.
150. Pouw MH, Hosman AJ, vanMiddendorp JJ et al. Biomarkers in spinal cord injury. Spinal Cord 2009; 47: 519–525.