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1.
背景:脊髓损伤后的神经再生和功能恢复一直是医学界研究的热点和难点。近几年随着研究的深入,细胞移植作为一种新的治疗方法,已经取得了一定的研究成果,但其临床疗效仍存在争议, 目的:应用循证医学Meta分析来评价细胞移植治疗晚期脊髓损伤的疗效。 方法:检索Cochrane图书馆(2010年第4期)、PubMed(1966/2010)、EMbase(1989/2010)、中国生物医学文献数据库(1978/2010)、万方数据库(1982/2010),纳入有关于细胞移植治疗晚期脊髓损伤患者的研究,两名调查员独立对文献质量进行严格评价和资料提取。脊髓损伤的患者接受细胞移植前后的美国脊髓损伤协会评分,包括运功、轻触觉、针刺觉。 结果与结论:共纳入7篇队列研究,共388例患者。Meta分析结果显示,脊髓损伤的患者细胞移植前后美国脊髓损伤协会功能评分差异有显著性意义(P < 0.000 01)。美国脊髓损伤协会运动评分移植前后差异有显著性意义[WMD=6.14,95%CI (3.43,8.85),P < 0.000 01],美国脊髓损伤协会轻触觉评分差异有显著性意义[WMD=8.63,95%CI (5.61,11.66),P < 0.000 01],美国脊髓损伤协会针刺觉评分差异有显著性意义[WMD=10.65,95%CI (7.58,13.72),P < 0.000 01]。细胞移植后无严重并发症。提示细胞移植可以作为晚期脊髓损伤的一种治疗手段,但是疗效和安全性仍需大样本的随机对照试验来验证。  相似文献   

2.
目的 观察自体骨髓干细胞移植治疗慢性脊髓损伤患者的临床疗效及安全性。方法 选择2010-01—2012-07江西省人民医院神经内科收治的慢性脊髓损伤患者28例,骨髓干细胞动员后,采自体骨髓干细胞进行鞘内注射移植治疗,骨髓干细胞数量(1.0~10.0)×107,1次/周,共治疗2次。分别于移植前和移植后1、3、12个月采用美国脊髓损伤学会(ASIA2000)制订的评分标准和改良的Barthel指数(MBI)评估疗效,并观察患者的不良反应。结果 MSCs移植1个月后,针刺痛觉评分、轻触觉评分、运动评分和MBI评分与入院时比较均明显改善(均P<0.05);移植3、12个月后各项评分与入院时比较均有显著差异(均P<0.01)。其中8例低热和3例低颅压性头痛,处理后症状完全消失。结论 自体MSCs移植治疗SCI可改善患者的运动和感觉功能,提高日常生活能力,且不良反应轻微。  相似文献   

3.
背景:临床常用皮质运动诱发电位和皮质体感诱发电位来分别评价脊髓损伤后运动传导路和感觉传导路的损伤或修复情况。 目的:以脊髓诱导电位监测骨髓间充质干细胞移植后急性脊髓完全性损伤大鼠下肢神经功能的变化。 方法:选取健康Wistar大鼠50只,分成5组,即生理盐水组、骨髓间充质干细胞移植组、脑源性神经营养因子修饰组、神经营养素3+骨髓间充质干细胞移植组和假手术组。除假手术组外,其余各组均制作Allen’s脊髓完全性损伤动物模型,造模后各组均行相应治疗。治疗后4,8和12周行大鼠后肢运动功能评分,并于造模后24 h,3,7,14 d行运动和体感诱发电位检测。 结果与结论:运动诱发电位检测结果提示,各治疗组的运动功能均有不同程度的恢复,与生理盐水组间差异均有显著性意义(P < 0.05),大鼠后肢BBB评分也证实了各治疗组后肢运动功能明显优于生理盐水组(P < 0.05)。提示经脑源性神经营养因子修饰的骨髓间充质干细胞可移植到脊髓损伤处,可改善大鼠的后肢运动,神经营养素3蛋白有可能提高骨髓间充质干细胞在体内的生存率,促进受损脊髓的轴突再生。  相似文献   

4.
背景:单纯的干细胞移植对脊髓损伤的修复作用并不理想,主要是因为脊髓损伤后损伤区域神经组织的水肿、缺血、缺氧等引起继发性损伤造成的。 目的:在骨髓间充质干细胞移植治疗大鼠脊髓损伤的同时应用吡拉西坦,观察两者对大鼠脊髓损伤恢复的影响。 方法:雌性Wistar大鼠参照改良Allen打击法制备大鼠脊髓损伤模型。随机分成3组,即单纯损伤组、骨髓间充质干细胞移植组及骨髓间充质干细胞移植联合吡拉西坦组。于伤后1,2,4,6,8周进行BBB评分和斜板实验等运动功能检测。第4周取材行病理切片苏木精-伊红染色,通过SRY-PCR检测雄性大鼠Y染色体上特有的基因SRY,从而得知移植骨髓间充质干细胞是否存活。8周后取材,行辣根过氧化物酶示踪观察,并通过透射电镜观察轴突的再生情况。 结果与结论:伤后4周,骨髓间充质干细胞移植组、联合治疗组大鼠后肢运动功能均有较明显恢复,联合治疗组较骨髓间充质干细胞移植组恢复快(P < 0.05)。单纯损伤组亦有所恢复,但程度较轻。病理切片单纯损伤组未见神经轴索通过;骨髓间充质干细胞移植组可见少量神经轴索样结构;联合治疗组可见较多神经轴索样结构。骨髓间充质干细胞移植组、联合治疗组有SRY基因表达,单纯损伤组未检测到SRY基因。辣根过氧化物酶阳性神经纤维数联合治疗组﹥骨髓间充质干细胞移植组>单纯损伤组,差异具有显著性意义(P < 0.05)。透射电镜下,骨髓间充质干细胞移植组、联合治疗组正中横断面可见新生的无髓及有髓神经纤维。提示骨髓间充质干细胞移植联合吡拉西坦促进大鼠损伤脊髓结构和功能恢复的效果明显优于单纯细胞移植组,两者联用具有协同效应。  相似文献   

5.
目的探讨脑桥出血早期患者脑皮质结构变化,并分析与感觉运动功能损伤的相关性。方法选择2014年5月至2015年3月本院接诊的16例脑桥出血患者进行研究将其作为观察组,选取同期16例健康者作为对照组。观察组患者入院后给予结构磁共振(MRI)检测,通过基于体素形态学方法对MRI的结构数据进行分析,比较两组患者大脑灰质体积区域的改变。并通过相关性分析患者脑皮质结构的改变与运动感觉功能的关系。结果两组患者在年龄与性别方面差异无统计学意义(P0.05);观察组的轻触觉评分、针刺觉评分以及运动评分均低于对照组,两组比较差异具有统计学意义(P0.001);基于体素形态学方法分析结果显示,观察组的双侧初级感觉中心、初级运动中心及其辅助运动区发生了灰质体积减小的现象(P0.05);观察组结构异常区域萎缩发生程度经相关分析与轻触觉评分、针刺觉评分以及运动评分无相关性(P0.05)。结论脑桥出血早期患者初级感觉中心、初级运动中心及其辅助运动区发生了灰质萎缩,但是萎缩程度与患者轻触觉评分、针刺觉评分以及运动评分无关。  相似文献   

6.
背景:骨髓间充质干细胞治疗脊髓损伤的研究已经逐渐由动物实验过渡到临床,但其作用机制还不完全清楚。 目的:观察骨髓间充质干细胞移植对脊髓损伤大鼠脊髓功能的修复作用,并通过临床应用观察短期疗效。 方法:采用改良Allen's打击法造成Wistar大鼠脊髓损伤模型,将体外分离培养的骨髓间充质干细胞分别经尾静脉及损伤局部移植,应用改良Tarlov评分评定大鼠行为学变化,在光镜下对损伤脊髓病理切片进行对比分析。对5例脊髓损伤患者通过损伤原位注射、腰穿、静脉输注的方式行人自体骨髓间充质干细胞移植,并行神经功能及生活能力评定。 结果与结论:治疗后15 d,骨髓间充质干细胞尾静脉及损伤局部移植组大鼠运动功能评分较模型对照组显著提高;移植后7,15,30 d,脊髓病理切片显示骨髓间充质干细胞尾静脉及损伤局部移植组大鼠较模型对照组有显著恢复。临床患者骨髓间充质干细胞移植后半年神经功能及生活能力均有改善。  相似文献   

7.
目的 评价大脑、骨髓和脂肪组织3种不同来源的神经干细胞对大鼠脊髓挫伤的治疗效果.方法 选取来源于同一大鼠成体中大脑、骨髓和脂肪的3个部位的组织,分离、诱导分化为不同来源的神经干细胞;应用自由落体损伤模型装置造成大鼠脊髓挫伤.将不同来源的神经干细胞分别移植入大鼠脊髓损伤部位,通过BBB评分比较修复脊髓损伤功能的效果,应用免疫荧光染色检测不同移植细胞在损伤脊髓中的存活、分布、迁移的情况.另设假手术对照组和生理盐水对照组.结果 与假手术对照组和生理盐水对照组比较,3个细胞处理组BBB评分在2~8周开始增加,9周以后更加明显,差异开始有统计学意义(P<0.05).在移植后1周和4周,细胞移植组中脑源性神经干细胞(SVZ-NSs)组Brdu/nestin+>神经元存活的数目明显高于其他2组.但差异没有统计学意义(P>0.05);到了第8周,3组均仅有少量Brdu/nestin+>细胞存活,相互之间比较差异无统计学意义(P>0.05).结论 植入来源于大脑、骨髓和脂肪组织的神经干细胞都可以在一定程度上提高脊髓损伤后运动功能恢复,但SVZ-NSs组的脊髓损伤大鼠运动功能恢复要比脂肪来源的神经干细胞(AD-NSs)组及骨髓来源的神经干细胞(BM-NSs)组更好.AD-NSs由于来源广泛和强有力的增殖能力,相比其他来源的神经干细胞,可能是更好的选择.  相似文献   

8.
移植人脐带间充质干细胞修复大鼠脊髓损伤   总被引:1,自引:0,他引:1  
背景:已知人脐带间充质干细胞对脊髓损伤存在着潜在的治疗价值,然而,当前对移植人脐带间充质干细胞治疗脊髓损伤及机制方面研究很少。 目的:观察人脐带间充质干细胞对脊髓损伤大鼠的治疗效果。 方法:40只Wistar大鼠建立脊髓损伤模型,38只造模成功后随机摸球法分为3组:空白对照组:只接受单纯损伤,不做任何移植;DMEM移植组:损伤后1周予以5 μL DMEM局部移植;细胞移植组:损伤后1周予以5 μL准备好的人脐带间充质干细胞局部移植(细胞数1×106)。移植后对实验动物通过BBB评分、体感诱发电位与运动诱发电位观察后肢功能恢复情况。分别于损伤后2,4,6,8,10周随机于细胞移植组抽取大鼠2只,免疫组织化学染色观察人脐带间充质干细胞存活、迁移、分化,通过胶质纤维酸性蛋白阳性细胞染色比较各组损伤局部胶质瘢痕形成面积。 结果与结论:BBB评分损伤后4周细胞移植组高于其他两组(P < 0.05),损伤后12周细胞移植组与其他两组相比SEP、MEP潜伏期缩短、波幅值增高(P < 0.05)。免疫组织化学染色示人脐带间充质干细胞可向神经元、星形胶质细胞和少突胶质细胞分化,分化的少突胶质细胞并包绕轴突形成髓鞘。细胞移植组损伤局部胶质瘢痕面积均小于其他两组(P < 0.05),空白对照组、DMEM移植组间差异无显著性(P > 0.05)。提示未经体外诱导的人脐带间充质干细胞可于损伤大鼠脊髓体内向神经元、星形胶质细胞、少突胶质细胞分化,减小胶质瘢痕,并促进脊髓损伤大鼠神经功能的恢复。  相似文献   

9.
目的探讨早期高压氧联合鼠神经生长因子对急性创伤性脊髓损伤患者神经及运动功能恢复的影响。方法70例急性创伤性脊髓损伤患者按数字表格法分为2组,各35例,对照组患者采取常规对症治疗,实验组在对照组基础上行早期高压氧联合鼠神经生长因子治疗,比较2组治疗后Frankel脊髓损伤分级、并发症发生率、治疗前后神经及运动功能恢复情况。结果实验组治疗后Frankel脊髓损伤功能恢复情况明显优于对照组(P0.05),2组治疗后针刺觉评分、触觉评分、BBB评分及Tarlov评分比较差异均有统计学意义(P0.05),2组并发症发生率(20.0%VS 22.9%)比较差异无统计学意义(P0.05)。结论早期高压氧联合鼠神经生长因子能明显改善急性创伤性脊髓损伤患者症状,促进患者神经及运动功能恢复,值得临床推广。  相似文献   

10.
背景:肌源性干细胞易于提取、分离及扩增,在特定条件下可分化为骨、软骨、肌肉等中胚层组织细胞,还可以跨胚层分化为神经细胞等,是组织工程临床用于脊髓损伤修复的理想种子细胞。 目的:观察肌源性干细胞移植对脊髓半切损伤大鼠运动功能的修复作用。 方法:40只成年SD大鼠随机数字表法分为移植组和对照组,每组20只。均进行脊髓半切损伤,伤后9 d,移植组于伤处移植体外转染绿色荧光蛋白基因的大鼠肌源性干细胞,而对照组仅注射等量PBS,于移植后1,2,3,4周用斜板实验和BBB评分测大鼠的运动功能,同时进行损伤脊髓取材、快速冰冻切片进行荧光显微镜观察。 结果与结论:所有大鼠脊髓半切损伤手术均成功,术后无动物死亡。肌源性干细胞移植后1周,移植组与对照组均有所恢复,斜板实验和BBB评分差异无显著性意义(P > 0.05);2~4周移植组恢复明显较好,斜板实验和BBB评分显著高于对照组(P < 0.05),移植组后肢活动与前后肢活动的协调性明显优于对照组。荧光显微镜观察经诱导分化和基因标记的肌源性干细胞在损伤脊髓组织局部生长良好,并且有沿着脊髓神经束向头尾两侧迁移的趋势。提示脊髓半切损伤大鼠经肌源性干细胞移植后能在损伤脊髓组织局部长期存活并明显改善其运动功能,肌源性干细胞移植对脊髓半切损伤大鼠有修复作用。 关键词:肌源性干细胞;移植;脊髓损伤;绿色荧光蛋白;大鼠  相似文献   

11.
背景:骨髓间充质干细胞移植对脊髓损伤有治疗作用,但其机制尚不完全清楚。 目的:应用免疫组织化学方法观察骨髓间充质干细胞静脉移植损伤脊髓局部脑源性神经营养因子及神经生长因子的表达,分析骨髓间充质干细胞移植治疗大鼠脊髓损伤的作用途径。 方法:运用改良Allen法制备T10脊髓外伤性截瘫大鼠模型,假手术组6只,脊髓损伤组24只随机分为对照组和骨髓间充质干细胞移植组。骨髓间充质干细胞移植组、假手术组接受骨髓间充质干细胞单细胞悬液1 mL(1×106 cells)自大鼠尾静脉缓慢注射移植,对照组静脉注射PBS 1 mL。 结果与结论:脊髓损伤后损伤局部的脑源性神经营养因子、神经生长因子表达增加,骨髓间充质干细胞静脉注射移植后能促进脊髓损伤局部脑源性神经营养因子、神经生长因子更进一步的表达,这可能是促进神经结构及神经功能恢复的因素之一。  相似文献   

12.
We examined the restorative effect of modified biodegradable chitin conduits in combination with bone marrow mesenchymal stem cell transplantation after right spinal cord hemisection injury. Immunohistochemical staining revealed that biological conduit sleeve bridging reduced glial scar formation and spinal muscular atrophy after spinal cord hemisection. Bone marrow mesenchymal stem cells survived and proliferated after transplantation in vivo, and differentiated into cells double-positive for S100(Schwann cell marker) and glial fibrillary acidic protein(glial cell marker) at 8 weeks. Retrograde tracing showed that more nerve fibers had grown through the injured spinal cord at 14 weeks after combination therapy than either treatment alone. Our findings indicate that a biological conduit combined with bone marrow mesenchymal stem cell transplantation effectively prevented scar formation and provided a favorable local microenvironment for the proliferation, migration and differentiation of bone marrow mesenchymal stem cells in the spinal cord, thus promoting restoration following spinal cord hemisection injury.  相似文献   

13.
人胚胎雪旺细胞脊髓内移植治疗晚期脊髓损伤   总被引:3,自引:0,他引:3  
目的 采用人胚雪旺细胞移植治疗晚期脊髓损伤,并探讨其疗效及安全性。方法 显微镜下切除脊髓损伤节段增厚的瘢痕组织,松解粘连,切开囊腔或空洞。取人胚胎背根神经节,培养成雪旺细胞并贴附于可吸收薇乔3-0紫色线及薇乔网的载体上,然后将其移植到脊髓损伤部位。本组共治疗53例,其中男42例,女11例,年龄2~58岁,伤后时间为4个月~19年。结果 雪旺细胞移植后2~8w时随访,按美国脊髓损伤学会(ASIA)脊髓损伤神经功能分类国际标准评价,53例患者的脊髓功能均有部分恢复,其中运动功能由术前(41.49±15.83)分提高到术后(44.62±15.39)分,轻触觉由(57.89±22.87)分提高到(63.94±23.67)分,针刺觉由(55.96±20.99)分提高到(59.68±20.57)分。患者术后无脊髓感染、功能损伤加重及死亡等并发症。术后复查MRI示脊髓无瘤样增生及空洞扩大。结论 人胚雪旺细胞移植治疗晚期脊髓损伤安全可行,能促进晚期脊髓损伤患者脊髓神经功能的部分恢复。  相似文献   

14.
As chondroitinase ABC can improve the hostile microenvironment and cell transplantation is proven to be effective after spinal cord injury, we hypothesized that their combination would be a more effective treatment option. At 5 days after T8 spinal cord crush injury, rats were injected with bone marrow mesenchymal stem cell suspension or chondroitinase ABC 1 mm from the edge of spinal cord damage zone. Chondroitinase ABC was first injected, and bone marrow mesenchymal stem cell suspension was injected on the next day in the combination group. At 14 days, the mean Basso, Beattie and Bresnahan score of the rats in the combination group was higher than other groups. Hematoxylin-eosin staining showed that the necrotic area was significantly reduced in the combination group compared with other groups. Glial fibrillary acidic protein-chondroitin sulfate proteoglycan double staining showed that the damage zone of astrocytic scars was significantly reduced without the cavity in the combination group. Glial fibrillary acidic protein/growth associated protein-43 double immunostaining revealed that positive fibers traversed the damage zone in the combination group. These results suggest that the combination of chondroitinase ABC and bone marrow mesenchymal stem cell transplantation contributes to the repair of spinal cord injury.  相似文献   

15.
We compared the effects of hematopoietic stem cell and marrow stromal cell transplantation for spinal cord injury in mice. From green fluorescent protein transgenic mouse bone marrow, lineage-negative, c-kit- and Sca-1-positive cells were sorted as hematopoietic stem cells and plastic-adherent cells were cultured as marrow stromal cells. One week after injury, hematopoietic stem cells or marrow stromal cells were injected into the lesioned site. Functional recovery was assessed and immunohistochemistry was performed. In the hematopoietic stem cell group, a portion of green fluorescent protein-positive cells expressed glial marker. In the marrow stem cell group, a number of green fluorescent protein and fibronectin-double positive cells were observed. No significant difference was observed in the recovery between both groups. Both hematopoietic stem cells and marrow stromal cells have the potential to restore the injured spinal cord and to promote functional recovery.  相似文献   

16.
Propofol is a neuroprotective anesthetic. Whether propofol can promote spinal cord injury repair by bone marrow mesenchymal stem cells remains poorly understood. We used rats to investigate spinal cord injury repair using bone marrow mesenchymal stem cell transplantation combined with propofol administration via the tail vein. Rat spinal cord injury was clearly alleviated; a large number of newborn non-myelinated and myelinated nerve fibers appeared in the spinal cord, the numbers of CM-Dil-labeled bone marrow mesenchymal stem cells and fluorogold-labeled nerve fibers were increased and hindlimb motor function of spinal cord-injured rats was markedly improved. These improvements were more prominent in rats subjected to bone marrow mesenchymal cell transplantation combined with propofol administration than in rats receiving monotherapy. These results indicate that propofol can enhance the therapeutic effects of bone marrow mesenchymal stem cell transplantation on spinal cord injury in rats.  相似文献   

17.
为探讨晚期脊髓损伤许旺细胞移植前后MRI特征及其临床意义,回顾性分析38例晚期脊髓损伤患者许旺细胞移植前后的MRI特征,并采用ASIA评分评价神经功能。移植前38例在MRI上均显示脊髓软化囊性变,平均体积为(7.61±9.38) mm3,移植后10例软化囊性变消失,其余28例软化囊性变均有缩小,平均体积缩小至(5.96±7.56) mm3 (P < 0.05)。移植后脊髓功能均有部分恢复,运动评分由移植前(41.56±16.68)分提高至移植后(44.15±17.14)分(P < 0.05);针刺觉评分由移植前(58.85±23.45)分提高至移植后(65.50±23.85)分(P < 0.05);轻触觉评分由移植前(56.56±23.43)分提高至移植后(65.75±23.25)分(P < 0.05),提示MRI能较好反映许旺细胞移植前后脊髓的形态学特征,脊髓软化囊性变的缩小或消失可作为判断许旺细胞移植成活的一个重要指标。  相似文献   

18.
Bone marrow mesenchymal stem cells can differentiate into neurons and astrocytes after trans- plantation in the spinal cord of rats with ischemia/reperfusion injury. Although bone marrow mesenchymal stem cells are known to protect against spinal cord ischemia/reperfusion injury through anti-apoptotic effects, the precise mechanisms remain unclear. In the present study, bone marrow mesenchymal stem cells were cultured and proliferated, then transplanted into rats with ischemia/reperfusion injury via retro-orbital injection. Immunohistochemistry and immunofluorescence with subsequent quantification revealed that the expression of the axonal regeneration marker, growth associated protein-43, and the neuronal marker, microtubule-as- sociated protein 2, significantly increased in rats with bone marrow mesenchymal stem cell transplantation compared with those in rats with spinal cord ischemia/reperfusion injury. Fur- thermore, the expression of the autophagy marker, microtubule-associated protein light chain 3B, and Beclin 1, was significantly reduced in rats with the bone marrow mesenchymal stem cell transplantation compared with those in rats with spinal cord ischemia/reperfusion injury. Western blot analysis showed that the expression of growth associated protein-43 and neuro- filament-H increased but light chain 3B and Beclin 1 decreased in rats with the bone marrow mesenchymal stem cell transplantation. Our results therefore suggest that bone marrow mes- enchymal stem cell transplantation promotes neurite growth and regeneration and prevents autophagy. These responses may likely be mechanisms underlying the protective effect of bone marrow mesenchymal stem cells against spinal cord ischemia/reperfusion injury.  相似文献   

19.
OBJECTIVE:To identify global research trends of stem cell transplantation for treating spinal cord injury using a bibliometric analysis of the Web of Science.DATA RETRIEVAL:We performed a bibliometric analysis of data retrievals for stem cell transplantation for treating spinal cord injury from 2002 to 2011 using the Web of Science.SELECTION CRITERIA:Inclusion criteria:(a) peer-reviewed articles on stem cell transplantation for treating spinal cord injury that were published and indexed in the Web of Science;(b) type of articles:original research articles,reviews,meeting abstracts,proceedings papers,book chapters,editorial material,and news items;and(c) year of publication:2002-2011.Exclusion criteria:(a) articles that required manual searching or telephone access;(b) documents that were not published in the public domain;and(c) a number of corrected papers from the total number of articles.MAIN OUTCOME MEASURES:(1) Annual publication output;(2) distribution according to country;(3) distribution according to institution;(4) distribution according to journals;(5) distribution according to funding agencies;and(6) top cited articles over the last 10 years.RESULTS:Bone marrow mesenchymal stem cells and embryonic stem cells have been widely used for treating spinal cord injury.In total,191 studies of bone marrow mesenchymal stem cell transplantation and 236 studies of embryonic stem cell transplantation for treating spinal cord injury appeared in the Web of Science from 2002 to 2011,and almost half of which were derived from American or Japanese authors and institutes.The number of studies of stem cell transplantation for treating spinal cord injury has gradually increased over the past 10 years.Most papers on stem cell transplantation for treating spinal cord injury appeared in journals with a particular focus on stem cell research,such as Stem Cells and Cell Transplantation.Although umbilical cord blood stem cells and adipose-derived stem cells have been studied for treating spinal cord injury,the number of published papers was much smaller,with only 21 and 17 records,respectively,in the Web of Science.CONCLUSION:Based on our analysis of the literature and research trends,we found that stem cells transplantation obtained from various sources have been studied for treating spinal cord injury;however,it is difficult for researchers to reach a consensus on this theme.  相似文献   

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