A systematic review of stem cells in treatment of spinal cord injury and a network Meta-analysis of the therapeutic effects via different transplantation ways

doi:10.3969/j.issn.2095-4344.2017.29.026

Abstract

Abstract:

BACKGROUND: Stem cell transplantation has been used in the clinical treatment of spinal cord injury. However, the efficacy and safety are still controversial. Although there are many approaches for stem cell transplantation, which one is better is unclear as yet.
OBJECTIVE: To systematically evaluate the efficacy and safety of stem cell transplantation for spinal cord injury, and to compare the therapeutic difference in stem cell transplantation via different approaches.
METHODS: A computer-based online search was conducted in PubMed, The Cochrane Library (Issue 4, 2016), Embase, CNKI, VIP, CBM, and Wan-Fang databases up to May 13, 2016 to screen the relevant randomized clinical controlled trials of stem cells in the treatment of spinal cord injury. Two reviewers independently selected the studies, extracted information, and assessed the quality of included trials. Data extracted from eligible studies was pooled and meta-analyzed using Stata13.1 and Gemtc0.14.3 software.
RESULTS AND CONCLUSION: A total of 10 randomized controlled trials involving 546 patients (294 in stem cells group and 252 in rehabilitation treatment group) were included. The results of meta-analysis showed that stem cell transplantation had an advantage over rehabilitation treatment in increasing American Spinal Cord Injury Association (ASIA) motor score, ASIA sensory score, Barthel Index, and decreasing the bladder residual urine volume. The incidence of low fever, abdominal distension, headache, lower limb numbness, and meningeal irritation was 14%, 7%, 7%, 8%, and 7%, respectively. Taking the rehabilitation treatment as a common reference, the results of the network meta-analysis showed that there were no significant differences in ASIA motor score, ASIA sensory score, Barthel Index, and incidence of complications among subarachnoid injection, intravenous injection, and intralesional injection. Compared with the rehabilitation treatment, only stem cell transplantation via subarachnoid injection had significant differences in ASIA motor score [MD=9.77, 95%CI (0.26, 21.46)], and ASIA sensory score [MD=25.79, 95%CI (10.07, 45.27)]. To conclude, the stem cells transplantation via subarachnoid injection is considered the most effective transplantation method. Due to the limitations of the included studies, more high-quality randomized controlled trials are required to verify the above conclusion. In addition, future studies should focus on the long-term efficacy and safety of stem cell transplantation in the treatment of spinal cord injury, and should investigate the clinical effects on spinal cord injury with different ASIA grades, types of stem cells, and transplantation time.

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

Key words: Stem Cells, Spinal Cord Injuries, Transplantation, Computer Systems, Meta-analysis, Tissue Engineering

CLC Number:

R394.2

Liu Ying, Liu Chu-fan, Zhang Hui-ting, Shi Ye, Lan Shan, Tang Ling-ling, Ai Jin-wei, Pei Bin. A systematic review of stem cells in treatment of spinal cord injury and a network Meta-analysis of the therapeutic effects via different transplantation ways[J]. Chinese Journal of Tissue Engineering Research, 2017, 21(29): 4748-4756.

Figures/Tables 3

2.3 纳入研究方法质量学评价纳入的10个随机临床对照试验质量评价见表2。按改良Jadad量表，3个研究得分3分[16，18，20]，7个研究得分5分[17，19，21-25]，10个研究平均分为4.40分，总体为高质量研究。 2.4 两种方法比较治疗脊髓损伤Meta分析结果 2.4.1 ASIA运动功能评分 9个研究报告了ASIA运动功能评分[17-19，21-25]，合计样本量422例，干细胞治疗组232例，康复理疗组190例。5个研究报告了治疗1个月的ASIA运动功能评分[19，21-23]，合并结果显示两组疗效差异无统计学意义[I2=0，MD=0.11，95%CI(-0.14，0.37)]；7个研究报告了治疗3个月的ASIA运动功能评分[18-23]，合并结果显示干细胞治疗组ASIA运动功能评分高于康复理疗组[I2=0，MD=0.21，95%CI(0.01，0.41)]；7个研究报报告了治疗6个月的ASIA运动功能评分[16，19，20，23-25]，合并结果显示干细胞治疗组ASIA运动功能评分高于康复理疗组[I2=0，MD=0.71，95%CI(0.50，0.92)]，见图1。 2.4.2 ASIA感觉功能评分 11个研究报告了ASIA感觉功能评分[16-25]，合计样本量546例，干细胞治疗组294例，康复理疗组252例。5个研究报告了治疗1个月的ASIA感觉功能评分[19，21-23]，合并结果显示两组疗效差异无统计学意义[I2=0，MD=0.13，95%CI(-0.12，0.38)]；7个研究报告了治疗3个月的ASIA感觉功能评分[17-19，21-23]，合并结果显示干细胞治疗组ASIA感觉功能评分高于康复理疗组[I2=0.0%，MD=0.47，95%CI(0.27，0.68)]；7个研究报告了治疗6个月的ASIA感觉功能评分[16，19-20，23-25]，合并结果显示干细胞治疗组ASIA感觉功能评分高于康复理疗组[I2=29.7%，MD=0.66，95%CI(0.44，0.87)]，见图2。 2.4.3 BI生活能力评分 7个研究报告BI生活能力评分[16-18，20-22，24]，合计样本量346例，干细胞治疗组169例，康复理疗组177例。2个研究报告了治疗1个月的BI生活能力评分[21-22]，合并结果显示两组疗效差异无统计学意义[I2=0，MD=0.04，95%CI(-0.48，0.55)]；4个研究报告了治疗3个月的BI生活能力评分[17-18，21-22]，合并结果显示干细胞治疗组BI生活能力评分高于康复理疗组[I2=4.2%，MD=0.57，95%CI(0.28，0.85)]；3个研究报告了治疗6个月的BI生活能力评分[16，20，24]，合并结果显示干细胞治疗组BI生活能力评分高于康复理疗组[I2=0，MD=0.57，95%CI(0.24，0.90)]，见图3。"

2.4.4 膀胱残余尿量 3个研究报告了膀胱残余尿量[21-22，25]，合计样本量98例，干细胞治疗组47例，康复理疗组51例。2个研究报告了治疗1个月的膀胱残余尿量[21-22]，合并结果显示两组疗效差异无统计学意义[I2=0，MD=-0.40，95%CI(-0.92，0.12)]；2个研究报告了治疗3个月的膀胱残余尿量[21- 22]，合并结果显示干细胞治疗组膀胱残余尿量少于康复理疗组[I2=41%，MD=-0.58，95%CI(-1.11，-0.05)]；1个研究报告了治疗6个月的膀胱残余尿量[25]，合并结果显示干细胞治疗组膀胱残余尿量少于康复理疗组[MD=-1.00，95%CI(-1.66，-0.34)] ，见图4。 2.4.5 并发症发生率 8个研究报告了治疗过程中并发症率[17-19，21-25]，合计样本量386例，干细胞治疗组79例，康复理疗组81例。并发症主要包括低热、腹胀、头痛、下肢麻木、脑膜刺激征等。Meta分析结果显示，干细胞治疗过程中发热(低热)发生率为14%[95%CI(5%，22%)]，腹胀发生率为7% [95%CI(0，17%)]，头痛腹胀发生率为7%[95%CI (1%，12%)]，下肢麻木(蛛网膜下腔注射)发生率为8% [95%CI (1%，15%)]，脑膜刺激征(蛛网膜下腔注射)发生率为7% [95%CI(3%，17%)]。 2.5 不同移植途径疗效比较Meta分析结果 2个研究注射方法描述为“蛛网膜下腔注射或静脉注射”[21-22]，1个研究未描述具体细胞移植途径[16]，予以排除。1个研究为3臂试验[19]，故含9个两两比较。以ASIA运动功能评分、ASIA感觉功能评分、BI生活能力评分和并发症发生率为结局指标，以综合康复理疗为共同对照进行网状Meta分析。干预措施间比较证据网络图以ASIA运动功能评分为例见图5。因纳入比较数量较少，未行小样本效应检测。各结局指标证据网络图均形成1个“康复理疗-蛛网膜下腔注射-静脉注射”三角形闭环，IF下限均为0，说明闭环一致性好。MCMC拟合一致模型模型结果显示：3种干细胞移植途径间比较，在ASIA运动功能评分、ASIA感觉功能评分、BI生活能力评分和并发症率方面差异均无统计学意义，见表3，4；与康复理疗比较，仅干细胞蛛网膜下腔注射在改善ASIA运动功能评分[MD=9.77，95%CI(0.26，21.46)优于综合康复理疗。运用MCMC拟合不一致模型进行敏感性分析，各治疗措施间比较结果未发生明显变化，说明本研究结果是稳定的。"

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