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中华关节外科杂志(电子版) ›› 2018, Vol. 12 ›› Issue (05) : 644 -652. doi: 10.3877/cma.j.issn.1674-134X.2018.05.009

所属专题： 文献；

临床论著

富血小板血浆联合间充质干细胞治疗膝骨关节炎的疗效
哈承志1, 李伟1, 任少达2, 周长辉2, 陈双峰2, 王大伟1,†(), 刘超3   
  1. 1. 252000　聊城，山东大学附属聊城市人民医院关节外科
    2. 252000　聊城，山东大学附属聊城市人民医院中心实验室
    3. 271000　泰安，泰山医学院
  • 收稿日期:2017-10-26 出版日期:2018-10-01
  • 通信作者: 王大伟
  • 基金资助:
    国家自然科学基金青年基金(81600087)

Effect of platelet rich plasma combined with mesenchymal stem cells in treatment of knee osteoarthritis

Chengzhi Ha1, Wei Li1, Shaoda Ren2, Changhui Zhou2, Shuangfeng Chen2, Dawei Wang1,†(), Chao Liu3   

  1. 1. Department of Joint Surgery, Liaocheng People’s Hospital, Shandong University, Liaocheng 252000, China
    2. Department of Central Laboratory, Liaocheng People’s Hospital, Shandong University, Liaocheng 252000, China
    3. Taishan Medical College, Taian 271000, China
  • Received:2017-10-26 Published:2018-10-01
  • Corresponding author: Dawei Wang
  • About author:
    Corresponding author: Wang Dawei, Email:
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引用本文：

哈承志, 李伟, 任少达, 周长辉, 陈双峰, 王大伟, 刘超. 富血小板血浆联合间充质干细胞治疗膝骨关节炎的疗效[J]. 中华关节外科杂志(电子版), 2018, 12(05): 644-652.

Chengzhi Ha, Wei Li, Shaoda Ren, Changhui Zhou, Shuangfeng Chen, Dawei Wang, Chao Liu. Effect of platelet rich plasma combined with mesenchymal stem cells in treatment of knee osteoarthritis[J]. Chinese Journal of Joint Surgery(Electronic Edition), 2018, 12(05): 644-652.

目的

观察关节腔内联合注射富血小板血浆与脐带间充质干细胞治疗轻中度膝关节骨关节炎患者的近期疗效。

方法

收集聊城市人民医院膝关节骨关节炎患者200例，纳入标准：Kellgren-Lawrence分级1～3级膝关节骨关节炎患者；排除标准：Kellgren-Lawrence分级4级骨关节炎患者及炎症性关节炎患者等。根据电脑产生的伪随机数字，将研究对象随机分为富血小板血浆(PRP)与脐带间充质干细胞(MSC)联合注射组(PRP＋MSC)、单纯PRP注射组(PRP组)、单纯脐带MSC注射组(MSC组)、玻璃酸钠(SH)注射组(SH组)，每组各50例。PRP ＋ MSC组关节腔内注射5 ml富血小板血浆与脐带间充质干细胞混合液；PRP组关节腔内注射5 ml富血小板血浆；MSC组关节腔内注射5 ml脐带间充质干细胞；SH组关节腔内注射2.5 ml的SH及曲安奈德注射液。分别在治疗后1、3、6、12个月进行随访，通过视觉疼痛模拟评分(VAS)，美国膝关节协会评分( AKS )评价治疗后膝关节功能的改善情况；采用酶联免疫吸附法检测治疗前后关节液中细胞因子的变化情况；利用MRI的T2 Map序列评价治疗前后关节软骨的变化情况。患者年龄、病程、VAS评分、AKS评分、细胞因子含量等计数资料分析采用单因素方法分析，患者性别比例、病情程度等计数资料分析采用卡方检验。

结果

200例患者中，175例完成随访，PRP ＋ MSC组45例，PRP组44例，MSC组43例，SH组43例。4组患者治疗前VAS、AKS及关节液中细胞因子的表达无统计学意义(P >0.05)。治疗后1个月，4组患者的VAS评分均较前降低，AKS评分较前升高，组内差异具有统计学意义(t ＝6.45，P <0.01)，组间差异无统计学意义(P >0.05)。3个月后，SH组VAS、AKS趋向于治疗前状态，其余3组未见反弹，PRP ＋ MSC联合注射组优于单纯PRP与MSC治疗组，4组间的差异具有统计学意义(F ＝7.84/4.35，P <0.01)。治疗后3周，SH组关节液中细胞因子未见明显改变，PRP ＋ MSC组关节液中细胞因子变化水平高于单纯PRP与MSC组，差异具有统计学意义(F ＝39.21，P <0.01)。治疗后6个月，MRI的T2Map序列显示PRP＋MSC组、PRP组、MSC组、SH组的平均软骨T2值分别为(54.07±2.64)ms、(56.59±1.40)ms、(56.40±1.57)ms、(57.98±1.95)ms，差异具有统计学意义(F＝30.63，P<0.05)。

结论

关节腔内联合注射富血小板血浆与脐带间充质干细胞明显改善膝关节骨关节炎患者的症状，延缓骨关节炎的进展。

关键词: 骨关节炎, 间质干细胞, 富血小板血浆
Objective

To observe the short-term efficacy of intra-articular injection of platelet-rich plasma(PRP) and umbilical cord mesenchymal stem cells(MSCs) in the treatment of mild to moderate knee osteoarthritis.

Methods

A total of 200 cases of osteoarthritis of knee joint in Liaocheng People′s Hospital were collected. Inclusion creteria: Kellgren- Lawrence grade Ⅰ to Ⅲ patients with osteoarthritis of knee joint. Exclusion criteria: Kelgren-Lawrence grade Ⅳ osteoarthritis patients and inflammatory arthritis patients. According to the pseudo-random numbers generated by the computer, the patients with knee osteoarthritis were randomly divided into PRP+ MSC group, PRP group, MSC group and sodium hyaluronate (SH) group, 50 cases in each group. In PRP+ MSC group, 5 ml PRP and umbilical cord MSCs mixture were injected into articular cavity; in PRP group, 5 ml PRP was injected into articular cavity; in MSC group, 5 ml umbilical cord MSCs were injected into articular cavity; in SH group, 2.5 ml SH and triamcinolone acetonide injection were injected into articular cavity. After one, three, six and 12 months of treatment, the improvement of knee joint function was evaluated by visual analogue scale (VAS) and American Knee Association score (AKS); the changes of cytokines in joint fluid were detected by enzyme-linked immunosorbent assay (ELISA), and the Changes in articular cartilage before and after were evaluated by T2 Map sequence of MRI. Measurement data such as age, course, VAS score, AKS score, and cytokine content were analyzed by one-way ANOVA. Enumeration data such as sex ratio and disease degree of patients were analyzed by chi-square test.

Results

Among the 200 patients, 175 were followed up, 45 in PRP+ MSC group, 44 in PRP group, 43 in MSC group and 43 in SH group. There was no significant difference in the expression of cytokines in VAS, AKS and synovial fluid between the four groups before treatment (P >0.05). One month after treatment, the VAS scores of the four groups were lower than before, and the AKS scores were higher than before. There was significant difference between the groups (t=6.45, P <0.01), and there was no significant difference between the groups (P >0.05). Three months later, VAS and AKS in SH group tended to be in the pre-treatment state, while no rebound was found in the other three groups. PRP+ MSC combined injection group was superior to PRP alone and MSC treatment groups. The difference between the four groups was statistically significant (F=7.84, 4.35; P <0.01). Three weeks after treatment, there was no significant change of cytokines in the joint fluid of SH group. The level of cytokines in the joint fluid of PRP+ MSC group was higher than that of PRP and MSC group (F=39.21, P <0.01). Six months after treatment, the average cartilage T2 values of PRP+ MSC group, PRP group, MSC group and SH group were (54.1±2.6)ms, (56.6±1.4)ms, (56.4±1.6)ms, (58.0±2.0)ms, respectively (F=30.63; P <0.05).

Conclusion

Intra-articular injection of platelet-rich plasma and umbilical cord mesenchymal stem cells can significantly improve the symptoms of patients with knee osteoarthritis and delay the progress of osteoarthritis.

Key words: Osteoarthritis, Mesenchymal stromal cells, Platelet-rich plasma
图1 流式细胞仪检测细胞表面标记物。CD19、CD34、CD45、CD11b及HLA-ABC为阴性，CD29、CD44、CD73、CD90及CD105为阳性
表1 患者一般基本资料比较
分组 例数 性别(男/女) 年龄[岁，(±s)] BMI[kg/m2，(±s)] Kellgren-Lawrence分级(Ⅰ/Ⅱ/Ⅲ) 病程[月，(±s)] 伴随慢性疾病者(例)
PRP＋MSC组 45 15/30 56.8±6.1 25.5±2.0 10/15/20 26.5±3.4 14
PRP组 44 14/30 55.6±3.6 25.4±2.8 10/14/20 25.6±2.6 13
MSC组 43 12/31 57.0±3.2 25.8±3.3 11/11/21 27.3±2.7 12
SH组 43 11/32 56.2±6.7 24.9±1.6 9/15/19 26.2±3.8 12
统计值 ? χ2＝0.79 F＝0.67 F ＝1.09 χ2＝1.03 F ＝2.29 χ2＝0.15
P值 ? >0.05 >0.05 >0.05 >0.05 >0.05 >0.05
表2 治疗前后VAS评分的比较(±s)
分组 例数 治疗前 治疗后1个月 治疗后3个月 治疗后6个月 治疗后12个月
PRP＋MSC组 45 6.2±1.5 2.6±1.4 2.2±1.2 2.2±1.1 2.2±1.1
PRP组 44 6.3±1.4 3.1±1.1 2.6±0.7 2.6±0.6 2.7±0.6
MSC组 43 5.9±1.6 2.9±1.0 2.6±0.7 2.6±0.6 2.6±0.8
SH组 43 6.0±1.2 2.8±1.0 3.1±1.0 3.5±1.0 3.9±1.0
F值 ? 0.83 1.28 7.84 16.91 28.42
P值 ? >0.05 >0.05 <0.01 <0.01 <0.01
表3 治疗前后AKS评分的比较(±s)
分组 例数 治疗前 治疗后1个月 治疗后3个月 治疗后6个月 治疗后12个月
PRP＋MSC组 45 56±13 82±11 86±10 86±9 86±10
PRP组 44 55±6 82±8 82±7 82±7 82±7
MSC组 43 57±5 83±9 82±9 82±7 82±6
SH组 43 55±10 82±9 79±9 76±9 73±9
F值 ? 0.50 0.24 4.35 22.19 22.08
P值 ? >0.05 >0.05 <0.01 <0.01 <0.01
表4 治疗前后膝关节液中炎症因子的表达情况(±s)
分组 例数 治疗前 首次治疗后3周
IL-1β(ng/L) TNF-α(ng/L) PGE2 (ng/L) MMP-13(ng/L) 软骨寡聚基质蛋白(μg/L) IL-1β(ng/L) TNF-α(ng/L) PGE2 (ng/L) MMP-13(ng/L) 软骨寡聚基质蛋白(μg/L)
PRP＋MSC组 45 54.23±4.34 87.24±3.62 20.31±2.51 209.36±15.99 0.87±0.22 37.29± 10.07 58.74±13.17 12.52±3.17 161.96±27.22 0.45±0.21
PRP组 44 56.11±4.58 86.39±5.76 20.85±3.88 210.73±10.51 0.73±0.39 40.73± 6.32 66.86±5.70 14.56±1.91 178.93±8.66 0.56±0.29
MSC组 43 56.15±4.48 86.29±4.50 19.67±2.93 206.92±10.75 0.84±0.31 45.31± 6.59 67.83±5.18 14.07±2.89 183.16±15.14 0.59±0.35
SH组 43 55.70±4.07 85.88±2.89 19.34±2.34 204.18±16.37 0.81±0.22 54.27±5.17 85.77±3.05 19.14±2.88 201.73±17.29 0.77±0.19
F值 ? 16 0.7 1.9 1.7 1.6 39.2 82.8 40.7 30.1 9.4
P值 ? >0.05 >0.05 >0.05 >0.05 >0.05 <0.01 <0.01 <0.01 <0.01 <0.01
表5 治疗前后MRI关节软骨T2值的比较(±s)
? 例数 治疗前(ms) 治疗后6个月(ms)
PRP＋MSC组 45 58.1±2.3 54.1±2.6
PRP组 44 57.9±3.8 56.6±1.4
MSC组 43 57.9±3.6 56.4±1.6
SH组 43 57.4±2.5 58.0±2.0
F值 ? 0.47 30.63
P值 ? >0.05 <0.01
图2 治疗前1周右膝关节MRI T2MAP影像，白色框内示退化软骨表面呈现蓝色
图3 治疗后6个月右膝关节MRI T2MAP影像，白色框内示软骨表面呈现绿色为主，代表软骨退化的蓝色大部分消退
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