Adipose-derived stem cells for treating knee osteoarthritis: relevant clinical trials and registration

doi:10.3969/j.issn.2095-4344.0633

Abstract

Abstract:

BACKGROUND: Osteoarthritis is the most common joint disease in elderly populations. Promising therapy that can control or even reverse the course of disease effectively remains unrevealed. Clinical trials focusing on applying adipose-derived stem cells for treating knee osteoarthritis have been conducted in the last few years, while the safety and viability remain unknown.
OBJECTIVE: To summarize the completed and processing clinical trials in which adipose-derived stem cells are applied in treating knee osteoarthritis and to demonstrate the safety and efficiency.
METHODS: PubMed, MEDLINE, Web of Science and Clinicaltrails.gov were searched for studies applying adipose-derived stem cells in the treatment of knee osteoarthritis up to December 2017. Inclusion criteria included randomized controlled trials, cohort studies and case series providing detailed study design, clinical data and follow-up results. Outcome measures included level of evidence, study design, inclusion criteria for patients, protocol for adipose-derived stem cells, clinical outcomes and serious adverse events.
RESULTS AND CONCLUSION: Nine completed clinical trials (2 controlled studies, 2 dose-effect studies, 5 case series) were included. All studies reported a significant improvement after applying adipose-derived stem cells in pain management and joint function recovery and no serious adverse events were observed. These findings confirmed the effectiveness and safety of adipose-derived stem cells in the treatment of knee osteoarthritis, while these studies provided low-level evidence.

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: Osteoarthritis, Adipose Tissue, Stem Cells, Clinical Trial, Tissue Engineering

CLC Number:

R394.2

Pang Zhi-ying, Yin Feng, Yuan Feng. Adipose-derived stem cells for treating knee osteoarthritis: relevant clinical trials and registration[J]. Chinese Journal of Tissue Engineering Research, 2018, 22(29): 4729-4735.

Figures/Tables 2

2.1 已完成临床试验数据分析共有9篇已完成的临床试验文献报道，现将其试验设计列举见表1。Koh等[22]在韩国开展的临床试验中，入选标准为年龄 > 65岁，患者关节软骨损伤K-L评分Ⅱ级至Ⅲ级，非手术治疗3个月以上无效。总计入选30例患者，治疗方案是受试者在关节镜下灌洗后于受损最严重部位注射混合于3 mL富血小板血浆的4.2×107血管基质成分。随访2年后结果显示，受试者Lyshome评分(术前54.3±15.4，术后74.2±13.4)、目测类比(VAS)评分(术前4.7±1.6，术后1.7±1.4)、KOOS评分明显改善，部分患者(16例)术后2年进行了第2次关节镜手术，大部分受试者对血管基质成分注射的治疗效果呈“阳性”。证据等级为Ⅳ级。Bui等[23]在越南开展的临床试验中，入选标准为>18岁，患者关节软骨损伤K-L评分Ⅱ级至Ⅲ级，Lysholm评分<65分，药物或自体软骨移植治疗无效。总计入选21例患者，未设盲，治疗方案是注射血管基质成分+富血小板血浆，具体剂量未详述。随访6个月后结果显示，受试者在VAS评分(注射前7.6±0.5，注射后1.5±0.5)和Lysholm评分(注射前61±11，注射后82±8.1)方面有显著改善，MRI提示软骨厚度增厚，具体未详述。证据等级为Ⅳ级。 Jo等[24]在韩国开展的临床试验中，入选标准为18-75岁，患者关节软骨损伤K-L评分Ⅱ级至Ⅳ级，止痛药物治疗无效，VAS评分>4分，软骨损伤面积在2-6 cm2内。总计入选了18例患者，未设盲，分4组，3例接受低剂量(1×107)脂肪干细胞，3例接受中剂量(5×107)脂肪干细胞，3例接受高剂量(10×107)脂肪干细胞，注射 28 d后评估安全性，之后9例接受高剂量(10×107)脂肪干细胞。治疗方案是关节镜术后将各组不同用量的脂肪干细胞重悬于3 mL生理盐水，关节腔内注射。随访6个月后结果显示，高剂量组受试者在WOMAC评分(注射前54.2±5.2，注射后32.8±6.3)、VAS评分(注射前79.6±2.2，注射后44.2±6.3)、KSS评分(注射前47.2±2.6，注射后71.0±4.4)方面有显著改善，MRI提示软骨缺损面积明显减小，软骨总量增加。在对同一批受试者随访2年结果显示[24]，高剂量组受试者在WOMAC评分(注射前54.2±5.2，注射后19.0±5.5)、VAS评分(注射前79.6±2.2，注射后45.8±8.1)、KSS评分(注射前47.2±2.6，注射后79.3±4.7)方面有显著改善，改善程度较6个月随访差异更为明显。证据等级为Ⅱ级。 Fodor等[25]在美国开展的临床试验中，入选标准为20-70岁，患者关节软骨损伤K-L评分Ⅱ级至Ⅲ级，VAS评分>4分，既往治疗无效。总计入选6例患者，未设盲，治疗方案是受试者接受膝关节腔内14.1×106血管基质成分混合于3 mL乳酸林格溶液注射。随访1年后结果显示，受试者在WOMAC评分(注射前32.9 ±14.6，注射后9.4±10.1)、VAS评分(注射前5.9±1.2，注射后2.0±1.8)方面有明显改善，关节活动度[注射前(136.6±7.3)°，注射后3个月(143.6±6.7)°]略有改善，起立时间[注射前(5.4±1.6) s，注射后3个月(2.8±0.3) s]明显改善。证据等级为Ⅳ级。 Garza等[26]在美国开展的临床试验中，入选标准为20-70岁，患者关节软骨损伤K-L评分Ⅱ级至Ⅲ级，ASA评分Ⅰ级至Ⅱ级，体质量指数小于35 kg/m2，VAS评分>4。总计入选6例患者，未设盲，治疗方案是超声下关节腔内注射48.2×106血管基质成分。随访3个月后结果显示受试者PROMIS疼痛评分有明显改善。证据等级为Ⅳ级。 Pers等[27]在欧洲的临床试验中，入选标准为50-70岁，患者关节软骨损伤K-L评分Ⅲ级至Ⅳ级，持续12个月以上膝关节疼痛。总计入选18例患者，未设盲，低剂量组6例(2×106脂肪干细胞)，中剂量组6例(10×106脂肪干细胞)，高剂量组6例(50×106脂肪干细胞)。治疗方案是受试者接受超声下膝关节腔内注射混合于3.6%白蛋白的相应数量脂肪干细胞共5 mL。随访6个月后结果显示，各组受试者在WOMAC评分、SF-36评分等方面均显示出相比于注射前明显改善，影像学方面dGEMRIC和T1加权MRI未在受试者中得到一致性改变，11例受试者进行了组织学评分。证据等级为Ⅱ级。 Koh等[28]在韩国的随机对照试验中，入选标准为18-50岁，患者关节软骨损伤ICRS评分Ⅲ级至Ⅳ级。总计入选80例患者，骨微裂术组40例，骨微裂术+脂肪干细胞组40例，分组对受试者设盲。治疗方案是所有受试者接受关节镜手术，术中清除损伤软骨，在软骨下进行骨微裂术，术后骨微裂术+脂肪干细胞组注射4.97×106脂肪干细胞或等价的5.02×107血管基质成分1︰1混合于凝血酶-纤维蛋白原溶液注射在缺损软骨表面。随访2年后结果显示，受试者在MRI MOCART评分(骨微裂术+脂肪干细胞组：36.6±11.9，骨微裂术组：51.8±19.7)有明显改善，KOOS评分仅在部分量表(疼痛评分，骨微裂术+脂肪干细胞组：62.4±15.3，骨微裂术组：30.1± 14.7；症状评分，骨微裂术+脂肪干细胞组：32.3±7.2，骨微裂术组：27.8±6.8)有改善，Lyshome评分以及VAS评分明显改善，在57例进行第二次关节镜手术的受试者中，软骨损伤评级在两组间无显著差异，软骨损伤ICRS评分有明显改善。证据等级为Ⅱ级。 Nguyen等[29]在越南的随机对照试验中，入选标准为年龄>18岁，患者关节软骨损伤K-L评分Ⅱ级至Ⅲ级，Lysholm评分<65分，药物或自体软骨移植治疗无效。总计入选30例患者，血管基质成分组15例，对照组15例。治疗方案是所有受试者接受关节镜手术，术中清除损伤软骨，在软骨下进行骨微裂术，血管基质成分组注射混合于3 mL富血小板血浆的血管基质成分5 mL，对照组注射生理盐水。随访18个月后结果显示WOMAC评分、Lyshome评分以及VAS评分在两组间差异显著，MRI结果显示评分改变不一，在关节功能恢复方面明显改善。证据等级为Ⅱ级。 Bansal等[30]在印度开展的研究中，入选标准为年龄50岁以上，患者关节Brandt影像学评分Ⅰ级至Ⅱ级，疼痛持续3个月以上，WOMAC评分<75分。总计入选10例患者，未设盲，治疗方案是受试者接受5 mL重悬于生理盐水、与3 mL富血小板血浆混合的4.2×107血管基质成分关节腔内注射。随访2年后结果显示注射前后WOMAC评分明显改善，6 min步行距离改善，MRI显示软骨厚度改变不一。证据等级为Ⅳ级。作者认为，截止目前已完成的脂肪干细胞治疗膝关节骨性关节炎的临床试验仅停留在Ⅰ期临床阶段。以上文献共计入选了219例受试者，各个临床试验的入选标准以及排除标准大相径庭。在年龄组的选择上有3个试验入选了高龄人群，其余均采用18岁以上常规年龄组。在提供年龄数据的198例受试者中，平均年龄53.2岁，女性占68.1%。入选标准中包含且不限于：影像学标准、基于临床诊断的临床标准以及基于疼痛或功能评价的量表标准。在试验设计上，未采用严格的脂肪干细胞-空白对照试验，部分试验仅使用单组设计，1个试验观察脂肪干细胞剂量和疗效关系，2个试验观察脂肪干细胞联合其他治疗对比该治疗的差异。在盲法设计上，大部分临床试验使用了开放性试验，即未对受试者设盲，仅有1个临床试验设单盲。试验的主要目的是观察整个治疗过程中不良事件的发生率，以上临床试验均未报道与治疗相关的严重不良反应事件，以此证明膝关节注射脂肪干细胞或血管基质成分的安全性。在其他评估疗效的观察指标中，仅设单组观察脂肪干细胞疗效的前瞻性研究显示，应用脂肪干细胞治疗前后VAS评分、WOMAC评分、Lysholm评分、MRI软骨评估、患者行动能力等方面有显著差异[22-23，25-26，30]。作者认为这些前瞻性研究的病例数量较小(6-30例)，且存在混杂偏倚，即受试者在接受脂肪干细胞治疗前后的症状改善是由于各种其他混杂因素，如生活方式改善或安慰剂效应造成，因此这些未设对照的临床试验结果并无法准确评价脂肪干细胞治疗的有效性，其证据等级为Ⅳ级，等价于病例系列研究，对临床的指导意义有限。在设立对照组的临床试验结果中：2个剂量疗效试验中，1个结果显示对比注射前，在VAS评分、WOMAC评分等方面低剂量组(2×106脂肪干细胞)有着相较于其他剂量更显著的改善[27]，而另1个结果显示仅在高剂量组(10×107脂肪干细胞)观察到WOMAC评分的显著改善[24]。以上矛盾的结果无法对今后临床试验脂肪干细胞用量作出指导，因此作者认为需要结合动物实验以及更大规模的剂量效应临床试验数据证明其确切的剂量疗效关系，以此指导脂肪干细胞治疗骨关节炎试验方案的制定。2个应用其他疗法对照脂肪干细胞联合该疗法的试验中，均显示治疗后对比治疗前在VAS评分、WOMAC评分、Lysholm评分、MRI软骨评估等方面有显著差异，然而显著的组间差异仅在一些特定观察点(例如仅在18个月观察到显著差异而不是6个月或12个月)或是一些量表的亚组(例如KOOS量表中的KOOS疼痛量表以及症状量表中观察到显著差异，而不是KOOS活动量表或生活质量量表或运动量表)[24]。以上实验结果的统计学差异可以部分说明脂肪干细胞的有效性，然而因为试验设计中存在偏倚，包括量表本身的偏倚、未设盲法导致受试者或实验者的主观偏倚，受试者数量的不足造成的偏倚以及采用回顾性数据作为对照组造成的选择性偏倚，因此这些对照试验的结论难以令人信服。作者认为这些研究属于低质量随机对照试验，其确切临床意义和研究价值有待商榷。综上所述，所纳入的临床研究并不能证明脂肪干细胞治疗骨关节炎的有效性。 2.2 进行中临床试验数据分析共有9个临床试验正在进行，其试验设计列举见表2。作者认为现在正在进行的应用脂肪干细胞或血管基质成分治疗膝关节骨性关节炎的临床试验属于Ⅱ期临床试验。以上文献拟入选570例受试者，试验的入选标准与目前已完成的临床试验相仿，而在入选人数、盲法、对照组设计等方面做到了进一步完善。随机对照试验拟入选人数达到了40-200例；盲法上基本均对受试者设盲，更有1个试验拟做到三盲；Yin和The GID Group的试验中空白组的设计均做到了真正意义的空白对照。试验的主要目的仍是观察不良事件，其次是观察脂肪干细胞或血管基质成分在改善疼痛、功能、生活质量方面进行量表评估；在软骨修复方面进行MRI评估。由于缺少具体文献佐证，作者无法对这些临床试验进行证据分级，但可以肯定的是这些随机对照试验结果将会为是否应用脂肪干细胞治疗膝关节骨性关节炎作出定论。"

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