脊髓损伤再生修复的临床研究进展
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摘要
创伤性脊髓损伤会导致患者感觉运动功能的严重缺失,严重影响生活质量,给社会和家庭带来沉重负担.针对创伤性脊髓损伤目前主要集中于处理原发性创伤损伤以及通过康复训练提高生活自理能力等方法,而对于神经再生及运动功能恢复却未有有效方法.以干细胞及生物材料为核心的再生医学技术的发展,为创伤性脊髓损伤的再生修复提供了新的治疗的可能.再生医学修复脊髓损伤的研究已逐渐进入临床试验阶段,为脊髓损伤患者的治疗带来了希望.本文对干细胞或功能细胞以及生物材料治疗创伤性脊髓损伤的临床研究现状进行了综述.
Traumatic spinal cord injuries(SCIs) often lead to permanent loss of motor and sensory functions, seriously affecting patients' quality of life, and placing a heavy burden on families and society. At present, the clinical strategies for traumatic spinal cord injury mainly focus on the treatment of primary traumatic injury and improvement of self-care ability through rehabilitation training. However,there is no effective method for nerve regeneration and recovery of motor function. The development of regenerative medicine technology based on stem cells and biological materials has provided a new technical method for the regeneration and repair of traumatic spinal cord injury. Relevant research has gradually entered the clinical stage, bringing new hope for the rehabilitation of patients with spinal cord injury. This paper sorted and summarized clinical research based on the treatments of traumatic SCIs by stem cells/functional cells or biomaterials.
Traumatic spinal cord injuries(SCIs) often lead to permanent loss of motor and sensory functions, seriously affecting patients' quality of life, and placing a heavy burden on families and society. At present, the clinical strategies for traumatic spinal cord injury mainly focus on the treatment of primary traumatic injury and improvement of self-care ability through rehabilitation training. However,there is no effective method for nerve regeneration and recovery of motor function. The development of regenerative medicine technology based on stem cells and biological materials has provided a new technical method for the regeneration and repair of traumatic spinal cord injury. Relevant research has gradually entered the clinical stage, bringing new hope for the rehabilitation of patients with spinal cord injury. This paper sorted and summarized clinical research based on the treatments of traumatic SCIs by stem cells/functional cells or biomaterials.
引文
1 National Spinal Cord Injury Statistical Center. Facts and Figures at A Glance. Birmingham, AL:University of Alabama at Birmingham, 2017
2 Li J J, Zhou H J, Hong Y, et al. Spinal cord injuries in Beijing:A municipal epidemiological survey in 2002(in Chinese). Chin J Rehabil Theory Pract, 2004, 10:412–413[李建军,周红俊,洪毅,等. 2002年北京市脊髓损伤发病率调查.中国康复理论与实践, 2004, 10:412–413]
3 Pan J, Li X, Zeng C, et al. Retrospective study of acute spinal cord injury between 2005 and 2007 in Pudong New Area, Shanghai(in Chinese). J Tongji Univ(Medical Sci), 2009, 30:131–135[潘杰,李昕,曾诚,等. 2005~2007年上海市浦东新区脊柱脊髓损伤调查分析.同济大学学报(医学版), 2009, 30:131–135]
4 Ru Q C. Epidemiological study of spinal cord injury in Dalian(in Chinese). Master Dissertation. Dalian Medical University, 2014[茹庆超.大连市脊髓损伤流行病学调查研究.硕士学位论文.大连:大连医科大学, 2014]
5 Ning G Z. Study on epidemiology of spinal cord injury in Tianjin(in Chinese). Doctor Dissertation. Tianjin Medical University, 2012[宁广智.天津市脊髓损伤流行病学调查研究.博士学位论文.天津:天津医科大学, 2012]
6 Selvarajah S, Hammond E R, Haider A H, et al. The burden of acute traumatic spinal cord injury among adults in the united states:An update. J Neurotraum, 2014, 31:228–238
7 Elizei S S, Kwon B K. The translational importance of establishing biomarkers of human spinal cord injury. Neural Regen Res, 2017, 12:385
8 Furlan J C, Noonan V, Cadotte D W, et al. Timing of decompressive surgery of spinal cord after traumatic spinal cord injury:An evidence-based examination of pre-clinical and clinical studies. J Neurotraum, 2011, 28:1371–1399
9 Carlson G D, Minato Y, Okada A, et al. Early time-dependent decompression for spinal cord injury:Vascular mechanisms of recovery. J Neurotraum, 1997, 14:951–962
10 Fehlings M G, Vaccaro A, Wilson J R, et al. Early versus delayed decompression for traumatic cervical spinal cord injury:Results of the surgical timing in acute spinal cord injury study(stascis). PLoS ONE, 2012, 7:e32037
11 Evaniew N, Belley-C?téE P, Fallah N, et al. Methylprednisolone for the treatment of patients with acute spinal cord injuries:A systematic review and meta-analysis. J Neurotraum, 2016, 33:468–481
12 Saadoun S, Chen S, Papadopoulos M C. Intraspinal pressure and spinal cord perfusion pressure predict neurological outcome after traumatic spinal cord injury. J Neurol Neurosurg Psychiatry, 2017, 88:452–453
13 Wilson J R, Tetreault L A, Kwon B K, et al. Timing of decompression in patients with acute spinal cord injury:A systematic review. Glob Spine J, 2017, 7:95S–115S
14 Donovan J, Kirshblum S. Clinical trials in traumatic spinal cord injury. Neurotherapeutics, 2018, 15:654–668
15 Zhang S C, Wernig M, Duncan I D, et al. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol, 2001, 19:1129–1133
16 Reubinoff B E, Itsykson P, Turetsky T, et al. Neural progenitors from human embryonic stem cells. Nat Biotechnol, 2001, 19:1134–1140
17 Carpenter M K, Inokuma M S, Denham J, et al. Enrichment of neurons and neural precursors from human embryonic stem cells. Exp Neurol,2001, 172:383–397
18 Wichterle H, Lieberam I, Porter J A, et al. Directed differentiation of embryonic stem cells into motor neurons. Cell, 2002, 110:385–397
19 Nistor G I, Totoiu M O, 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
20 Brüstle O, Jones K N, Learish R D, et al. Embryonic stem cell-derived glial precursors:A source of myelinating transplants. Science, 1999, 285:754 –756
21 Keirstead H S, Nistor G, Bernal G, et al. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci, 2005, 25:4694–4705
22 Fawcett J W, Curt A, Steeves J D, et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the iccp panel:Spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord, 2007, 45:190–205
23 Gritti A, Parati E, Cova L, et al. Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor. J Neurosci, 1996, 16:1091–1100
24 Palmer T D, Takahashi J, Gage F H. The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci, 1997, 8:389–404
25 Weiss S, Dunne C, Hewson J, et al. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci, 1996, 16:7599–7609
26 Rosenzweig E S, Brock J H, Lu P, et al. Restorative effects of human neural stem cell grafts on the primate spinal cord. Nat Med, 2018, 24:484–490
27 Lu P, Wang Y, Graham L, et al. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell, 2012, 150:1264–1273
28 Mothe A J, Tator C H. Advances in stem cell therapy for spinal cord injury. J Clin Invest, 2012, 122:3824–3834
29 Anderson A J, Piltti K M, Hooshmand M J, et al. Preclinical efficacy failure of human CNS-derived stem cells for use in the pathway study of cervical spinal cord injury. Stem Cell Rep, 2017, 8:249–263
30 Curtis E, Martin J R, Gabel B, et al. A first-in-human, phase I study of neural stem cell transplantation for chronic spinal cord injury. Cell Stem Cell, 2018, 22:941–950
31 Jiang Y, Jahagirdar B N, Reinhardt R L, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature, 2002, 418:41–49
32 Chamberlain G, Fox J, Ashton B, et al. Concise review:Mesenchymal stem cells:Their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells, 2007, 25:2739–2749
33 Oh S K, Choi K H, Yoo J Y, et al. A phase III clinical trial showing limited efficacy of autologous mesenchymal stem cell therapy for spinal cord injury. Neurosurgery, 2016, 78:436–447
34 Pashoutan S D, Shamsasenjan K, Akbarzadehlaleh P. Mesenchymal stem cell-derived exosomes:New opportunity in cell-free therapy. Adv Pharm Bull, 2016, 6:293–299
35 Qu J, Zhang H. Roles of mesenchymal stem cells in spinal cord injury. Stem Cells Int, 2017, 2017:1–12
36 Oudega M, Xu X M. Schwann cell transplantation for repair of the adult spinal cord. J Neurotraum, 2006, 23:453–467
37 Kanno H, Pressman Y, Moody A, et al. Combination of engineered schwann cell grafts to secrete neurotrophin and chondroitinase promotes axonal regeneration and locomotion after spinal cord injury. J Neurosci, 2014, 34:1838–1855
38 Fraher J P. The transitional zone and CNS regeneration. J Anatomy, 1999, 194:161–182
39 Guest J, Santamaria A J, Benavides F D. Clinical translation of autologous Schwann cell transplantation for the treatment of spinal cord injury.Curr Opin Organ Transplantation, 2013, 18:682–689
40 Anderson K D, Guest J D, Dietrich W D, et al. Safety of autologous human Schwann cell transplantation in subacute thoracic spinal cord injury. J Neurotraum, 2017, 34:2950–2963
41 Führmann T, Anandakumaran P N, Shoichet M S. Combinatorial therapies after spinal cord injury:How can biomaterials help? Adv Healthcare Mater, 2017, 6:1601130
42 Shrestha B, Coykendall K, Li Y, et al. Repair of injured spinal cord using biomaterial scaffolds and stem cells. Stem Cell Res Ther, 2014, 5:91
43 Orive G, Anitua E, Pedraz J L, et al. Biomaterials for promoting brain protection, repair and regeneration. Nat Rev Neurosci, 2009, 10:682–692
44 Piantino J, Burdick J A, Goldberg D, et al. An injectable, biodegradable hydrogel for trophic factor delivery enhances axonal rewiring and improves performance after spinal cord injury. Exp Neurol, 2006, 201:359–367
45 Li X, Yang Z, Zhang A, et al. Repair of thoracic spinal cord injury by chitosan tube implantation in adult rats. Biomaterials, 2009, 30:1121–1132
46 Yang Z, Zhang A, Duan H, et al. Nt3-chitosan elicits robust endogenous neurogenesis to enable functional recovery after spinal cord injury. Proc Natl Acad Sci USA, 2015, 112:13354–13359
47 Burdick J A, Ward M, Liang E, et al. Stimulation of neurite outgrowth by neurotrophins delivered from degradable hydrogels. Biomaterials, 2006,27 :452–459
48 Fan J, Xiao Z, Zhang H, et al. Linear ordered collagen scaffolds loaded with collagen-binding neurotrophin-3 promote axonal regeneration and partial functional recovery after complete spinal cord transection. J Neurotraum, 2010, 27:1671–1683
49 Han Q, Jin W, Xiao Z, et al. The promotion of neural regeneration in an extreme rat spinal cord injury model using a collagen scaffold containing a collagen binding neuroprotective protein and an egfr neutralizing antibody. Biomaterials, 2010, 31:9212–9220
50 Han Q, Sun W, Lin H, et al. Linear ordered collagen scaffolds loaded with collagen-binding brain-derived neurotrophic factor improve the recovery of spinal cord injury in rats. Tissue Eng Part A, 2009, 15:2927–2935
51 Han S, Wang B, Jin W, et al. The collagen scaffold with collagen binding BDNF enhances functional recovery by facilitating peripheral nerve infiltrating and ingrowth in canine complete spinal cord transection. Spinal Cord, 2014, 52:867–873
52 Han S, Wang B, Jin W, et al. The linear-ordered collagen scaffold-BDNF complex significantly promotes functional recovery after completely transected spinal cord injury in canine. Biomaterials, 2015, 41:89–96
53 Fan C, Li X, Xiao Z, et al. A modified collagen scaffold facilitates endogenous neurogenesis for acute spinal cord injury repair. Acta Biomater,2017, 51:304–316
54 Marsh S E, Yeung S T, Torres M, et al. HuCNS-SC human NSCs fail to differentiate, form ectopic clusters, and provide no cognitive benefits in a transgenic model of alzheimer’s disease. Stem Cell Rep, 2017, 8:235–248
55 Yang H, Lu P, McKay H M, et al. Endogenous neurogenesis replaces oligodendrocytes and astrocytes after primate spinal cord injury. J Neurosci,2006, 26:2157–2166
56 Wang B, Xiao Z, Chen B, et al. Nogo-66 promotes the differentiation of neural progenitors into astroglial lineage cells through m TOR-STAT3pathway. PLoS ONE, 2008, 3:e1856
57 Kadoya K, Lu P, Nguyen K, et al. Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat Med,2016, 22:479–487
58 Xu B, Zhao Y, Xiao Z, et al. A dual functional scaffold tethered with EGFR antibody promotes neural stem cell retention and neuronal differentiation for spinal cord injury repair. Adv Healthcare Mater, 2017, 6:1601279
59 Lai B Q, Che M T, Du B L, et al. Transplantation of tissue engineering neural network and formation of neuronal relay into the transected rat spinal cord. Biomaterials, 2016, 109:40–54
60 Wu G H, Shi H J, Che M T, et al. Recovery of paralyzed limb motor function in canine with complete spinal cord injury following implantation of MSC-derived neural network tissue. Biomaterials, 2018, 181:15–34
61 Chen B, Xiao Z, Zhao Y, et al. Functional biomaterial-based regenerative microenvironment for spinal cord injury repair. Natl Sci Rev, 2017, 4:530 –532
62 Zhao Y, Xiao Z, Chen B, et al. The neuronal differentiation microenvironment is essential for spinal cord injury repair. Organogenesis, 2017, 13:63 –70
63 Theodore N, Hlubek R, Danielson J, et al. First human implantation of a bioresorbable polymer scaffold for acute traumatic spinal cord injury.Neurosurgery, 2016, 79:E305–E312
64 Xiao Z, Tang F, Zhao Y, et al. Significant improvement of acute complete spinal cord injury patients diagnosed by a combined criteria implanted with neuroregen scaffolds and mesenchymal stem cells. Cell Transplant, 2018, 27:907–915
65 Zhao Y, Tang F, Xiao Z, et al. Clinical study of neuroregen scaffold combined with human mesenchymal stem cells for the repair of chronic complete spinal cord injury. Cell Transplant, 2017, 26:891–900
66 Xiao Z, Tang F, Tang J, et al. One-year clinical study of neuroregen scaffold implantation following scar resection in complete chronic spinal cord injury patients. Sci China Life Sci, 2016, 59:647–655
67 Teng Y D, Lavik E B, 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
68 Slotkin J R, Pritchard C D, Luque B, et al. Biodegradable scaffolds promote tissue remodeling and functional improvement in non-human primates with acute spinal cord injury. Biomaterials, 2017, 123:63–76
69 Lin H, Chen B, Wang B, et al. Novel nerve guidance material prepared from bovine aponeurosis. J Biomed Mater Res, 2006, 79A:591–598
70 Han S, Li X, Xiao Z, et al. Complete canine spinal cord transection model:A large animal model for the translational research of spinal cord regeneration. Sci China Life Sci, 2018, 61:115–117
2 Li J J, Zhou H J, Hong Y, et al. Spinal cord injuries in Beijing:A municipal epidemiological survey in 2002(in Chinese). Chin J Rehabil Theory Pract, 2004, 10:412–413[李建军,周红俊,洪毅,等. 2002年北京市脊髓损伤发病率调查.中国康复理论与实践, 2004, 10:412–413]
3 Pan J, Li X, Zeng C, et al. Retrospective study of acute spinal cord injury between 2005 and 2007 in Pudong New Area, Shanghai(in Chinese). J Tongji Univ(Medical Sci), 2009, 30:131–135[潘杰,李昕,曾诚,等. 2005~2007年上海市浦东新区脊柱脊髓损伤调查分析.同济大学学报(医学版), 2009, 30:131–135]
4 Ru Q C. Epidemiological study of spinal cord injury in Dalian(in Chinese). Master Dissertation. Dalian Medical University, 2014[茹庆超.大连市脊髓损伤流行病学调查研究.硕士学位论文.大连:大连医科大学, 2014]
5 Ning G Z. Study on epidemiology of spinal cord injury in Tianjin(in Chinese). Doctor Dissertation. Tianjin Medical University, 2012[宁广智.天津市脊髓损伤流行病学调查研究.博士学位论文.天津:天津医科大学, 2012]
6 Selvarajah S, Hammond E R, Haider A H, et al. The burden of acute traumatic spinal cord injury among adults in the united states:An update. J Neurotraum, 2014, 31:228–238
7 Elizei S S, Kwon B K. The translational importance of establishing biomarkers of human spinal cord injury. Neural Regen Res, 2017, 12:385
8 Furlan J C, Noonan V, Cadotte D W, et al. Timing of decompressive surgery of spinal cord after traumatic spinal cord injury:An evidence-based examination of pre-clinical and clinical studies. J Neurotraum, 2011, 28:1371–1399
9 Carlson G D, Minato Y, Okada A, et al. Early time-dependent decompression for spinal cord injury:Vascular mechanisms of recovery. J Neurotraum, 1997, 14:951–962
10 Fehlings M G, Vaccaro A, Wilson J R, et al. Early versus delayed decompression for traumatic cervical spinal cord injury:Results of the surgical timing in acute spinal cord injury study(stascis). PLoS ONE, 2012, 7:e32037
11 Evaniew N, Belley-C?téE P, Fallah N, et al. Methylprednisolone for the treatment of patients with acute spinal cord injuries:A systematic review and meta-analysis. J Neurotraum, 2016, 33:468–481
12 Saadoun S, Chen S, Papadopoulos M C. Intraspinal pressure and spinal cord perfusion pressure predict neurological outcome after traumatic spinal cord injury. J Neurol Neurosurg Psychiatry, 2017, 88:452–453
13 Wilson J R, Tetreault L A, Kwon B K, et al. Timing of decompression in patients with acute spinal cord injury:A systematic review. Glob Spine J, 2017, 7:95S–115S
14 Donovan J, Kirshblum S. Clinical trials in traumatic spinal cord injury. Neurotherapeutics, 2018, 15:654–668
15 Zhang S C, Wernig M, Duncan I D, et al. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol, 2001, 19:1129–1133
16 Reubinoff B E, Itsykson P, Turetsky T, et al. Neural progenitors from human embryonic stem cells. Nat Biotechnol, 2001, 19:1134–1140
17 Carpenter M K, Inokuma M S, Denham J, et al. Enrichment of neurons and neural precursors from human embryonic stem cells. Exp Neurol,2001, 172:383–397
18 Wichterle H, Lieberam I, Porter J A, et al. Directed differentiation of embryonic stem cells into motor neurons. Cell, 2002, 110:385–397
19 Nistor G I, Totoiu M O, 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
20 Brüstle O, Jones K N, Learish R D, et al. Embryonic stem cell-derived glial precursors:A source of myelinating transplants. Science, 1999, 285:754 –756
21 Keirstead H S, Nistor G, Bernal G, et al. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci, 2005, 25:4694–4705
22 Fawcett J W, Curt A, Steeves J D, et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the iccp panel:Spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord, 2007, 45:190–205
23 Gritti A, Parati E, Cova L, et al. Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor. J Neurosci, 1996, 16:1091–1100
24 Palmer T D, Takahashi J, Gage F H. The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci, 1997, 8:389–404
25 Weiss S, Dunne C, Hewson J, et al. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci, 1996, 16:7599–7609
26 Rosenzweig E S, Brock J H, Lu P, et al. Restorative effects of human neural stem cell grafts on the primate spinal cord. Nat Med, 2018, 24:484–490
27 Lu P, Wang Y, Graham L, et al. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell, 2012, 150:1264–1273
28 Mothe A J, Tator C H. Advances in stem cell therapy for spinal cord injury. J Clin Invest, 2012, 122:3824–3834
29 Anderson A J, Piltti K M, Hooshmand M J, et al. Preclinical efficacy failure of human CNS-derived stem cells for use in the pathway study of cervical spinal cord injury. Stem Cell Rep, 2017, 8:249–263
30 Curtis E, Martin J R, Gabel B, et al. A first-in-human, phase I study of neural stem cell transplantation for chronic spinal cord injury. Cell Stem Cell, 2018, 22:941–950
31 Jiang Y, Jahagirdar B N, Reinhardt R L, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature, 2002, 418:41–49
32 Chamberlain G, Fox J, Ashton B, et al. Concise review:Mesenchymal stem cells:Their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells, 2007, 25:2739–2749
33 Oh S K, Choi K H, Yoo J Y, et al. A phase III clinical trial showing limited efficacy of autologous mesenchymal stem cell therapy for spinal cord injury. Neurosurgery, 2016, 78:436–447
34 Pashoutan S D, Shamsasenjan K, Akbarzadehlaleh P. Mesenchymal stem cell-derived exosomes:New opportunity in cell-free therapy. Adv Pharm Bull, 2016, 6:293–299
35 Qu J, Zhang H. Roles of mesenchymal stem cells in spinal cord injury. Stem Cells Int, 2017, 2017:1–12
36 Oudega M, Xu X M. Schwann cell transplantation for repair of the adult spinal cord. J Neurotraum, 2006, 23:453–467
37 Kanno H, Pressman Y, Moody A, et al. Combination of engineered schwann cell grafts to secrete neurotrophin and chondroitinase promotes axonal regeneration and locomotion after spinal cord injury. J Neurosci, 2014, 34:1838–1855
38 Fraher J P. The transitional zone and CNS regeneration. J Anatomy, 1999, 194:161–182
39 Guest J, Santamaria A J, Benavides F D. Clinical translation of autologous Schwann cell transplantation for the treatment of spinal cord injury.Curr Opin Organ Transplantation, 2013, 18:682–689
40 Anderson K D, Guest J D, Dietrich W D, et al. Safety of autologous human Schwann cell transplantation in subacute thoracic spinal cord injury. J Neurotraum, 2017, 34:2950–2963
41 Führmann T, Anandakumaran P N, Shoichet M S. Combinatorial therapies after spinal cord injury:How can biomaterials help? Adv Healthcare Mater, 2017, 6:1601130
42 Shrestha B, Coykendall K, Li Y, et al. Repair of injured spinal cord using biomaterial scaffolds and stem cells. Stem Cell Res Ther, 2014, 5:91
43 Orive G, Anitua E, Pedraz J L, et al. Biomaterials for promoting brain protection, repair and regeneration. Nat Rev Neurosci, 2009, 10:682–692
44 Piantino J, Burdick J A, Goldberg D, et al. An injectable, biodegradable hydrogel for trophic factor delivery enhances axonal rewiring and improves performance after spinal cord injury. Exp Neurol, 2006, 201:359–367
45 Li X, Yang Z, Zhang A, et al. Repair of thoracic spinal cord injury by chitosan tube implantation in adult rats. Biomaterials, 2009, 30:1121–1132
46 Yang Z, Zhang A, Duan H, et al. Nt3-chitosan elicits robust endogenous neurogenesis to enable functional recovery after spinal cord injury. Proc Natl Acad Sci USA, 2015, 112:13354–13359
47 Burdick J A, Ward M, Liang E, et al. Stimulation of neurite outgrowth by neurotrophins delivered from degradable hydrogels. Biomaterials, 2006,27 :452–459
48 Fan J, Xiao Z, Zhang H, et al. Linear ordered collagen scaffolds loaded with collagen-binding neurotrophin-3 promote axonal regeneration and partial functional recovery after complete spinal cord transection. J Neurotraum, 2010, 27:1671–1683
49 Han Q, Jin W, Xiao Z, et al. The promotion of neural regeneration in an extreme rat spinal cord injury model using a collagen scaffold containing a collagen binding neuroprotective protein and an egfr neutralizing antibody. Biomaterials, 2010, 31:9212–9220
50 Han Q, Sun W, Lin H, et al. Linear ordered collagen scaffolds loaded with collagen-binding brain-derived neurotrophic factor improve the recovery of spinal cord injury in rats. Tissue Eng Part A, 2009, 15:2927–2935
51 Han S, Wang B, Jin W, et al. The collagen scaffold with collagen binding BDNF enhances functional recovery by facilitating peripheral nerve infiltrating and ingrowth in canine complete spinal cord transection. Spinal Cord, 2014, 52:867–873
52 Han S, Wang B, Jin W, et al. The linear-ordered collagen scaffold-BDNF complex significantly promotes functional recovery after completely transected spinal cord injury in canine. Biomaterials, 2015, 41:89–96
53 Fan C, Li X, Xiao Z, et al. A modified collagen scaffold facilitates endogenous neurogenesis for acute spinal cord injury repair. Acta Biomater,2017, 51:304–316
54 Marsh S E, Yeung S T, Torres M, et al. HuCNS-SC human NSCs fail to differentiate, form ectopic clusters, and provide no cognitive benefits in a transgenic model of alzheimer’s disease. Stem Cell Rep, 2017, 8:235–248
55 Yang H, Lu P, McKay H M, et al. Endogenous neurogenesis replaces oligodendrocytes and astrocytes after primate spinal cord injury. J Neurosci,2006, 26:2157–2166
56 Wang B, Xiao Z, Chen B, et al. Nogo-66 promotes the differentiation of neural progenitors into astroglial lineage cells through m TOR-STAT3pathway. PLoS ONE, 2008, 3:e1856
57 Kadoya K, Lu P, Nguyen K, et al. Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat Med,2016, 22:479–487
58 Xu B, Zhao Y, Xiao Z, et al. A dual functional scaffold tethered with EGFR antibody promotes neural stem cell retention and neuronal differentiation for spinal cord injury repair. Adv Healthcare Mater, 2017, 6:1601279
59 Lai B Q, Che M T, Du B L, et al. Transplantation of tissue engineering neural network and formation of neuronal relay into the transected rat spinal cord. Biomaterials, 2016, 109:40–54
60 Wu G H, Shi H J, Che M T, et al. Recovery of paralyzed limb motor function in canine with complete spinal cord injury following implantation of MSC-derived neural network tissue. Biomaterials, 2018, 181:15–34
61 Chen B, Xiao Z, Zhao Y, et al. Functional biomaterial-based regenerative microenvironment for spinal cord injury repair. Natl Sci Rev, 2017, 4:530 –532
62 Zhao Y, Xiao Z, Chen B, et al. The neuronal differentiation microenvironment is essential for spinal cord injury repair. Organogenesis, 2017, 13:63 –70
63 Theodore N, Hlubek R, Danielson J, et al. First human implantation of a bioresorbable polymer scaffold for acute traumatic spinal cord injury.Neurosurgery, 2016, 79:E305–E312
64 Xiao Z, Tang F, Zhao Y, et al. Significant improvement of acute complete spinal cord injury patients diagnosed by a combined criteria implanted with neuroregen scaffolds and mesenchymal stem cells. Cell Transplant, 2018, 27:907–915
65 Zhao Y, Tang F, Xiao Z, et al. Clinical study of neuroregen scaffold combined with human mesenchymal stem cells for the repair of chronic complete spinal cord injury. Cell Transplant, 2017, 26:891–900
66 Xiao Z, Tang F, Tang J, et al. One-year clinical study of neuroregen scaffold implantation following scar resection in complete chronic spinal cord injury patients. Sci China Life Sci, 2016, 59:647–655
67 Teng Y D, Lavik E B, 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
68 Slotkin J R, Pritchard C D, Luque B, et al. Biodegradable scaffolds promote tissue remodeling and functional improvement in non-human primates with acute spinal cord injury. Biomaterials, 2017, 123:63–76
69 Lin H, Chen B, Wang B, et al. Novel nerve guidance material prepared from bovine aponeurosis. J Biomed Mater Res, 2006, 79A:591–598
70 Han S, Li X, Xiao Z, et al. Complete canine spinal cord transection model:A large animal model for the translational research of spinal cord regeneration. Sci China Life Sci, 2018, 61:115–117