Clinical progression of mesenchymal stem cells in the treatment of knee osteoarthritis

doi:10.3877/cma.j.issn.2095-1221.2021.06.007

Abstract

Abstract:

Knee osteoarthritis characterized by articular cartilage degeneration, meniscus wear and osteophyte formation is a degenerative disease of articular cartilage that is common in middle-aged and elderly people. Because of the lack of nourishment of nerves and joint microvasculature, articular cartilage can hardly heal or repair itself after undergoing degenerative changes. The effect of conservative treatment is unsatisfactory, and joint replacement has to be taken in late-stage and severe cases. Mesenchymal stem cells (MSCs) are reliable materials for tissue regeneration and repair because of multilineage differentiation potential and strong paracrine capacity. MSCs can be derived from fat, bone marrow and umbilical cord. Generally, it is separated and amplified in vitro, and injected into the knee joint cavity to improve arthritic symptoms. Numerous clinical trials of MSCs in the treatment of knee osteoarthritis have demonstrated its efficacy. This article collects literature and clinical trials of MSCs in the treatment of knee osteoarthritis from 2017 to 2020, through Pubmed, domestic literature database and clinicaltrials.gov. We also review the clinical research results, treatment effects, existing problems and development prospects.

Key words: Mesenchymal stem cells, Knee osteoarthritis, Intra-articular injection

Linjie Lv, Changsheng Wang, Xiaobing Wang, Zhong Li, Qijun Qian. Clinical progression of mesenchymal stem cells in the treatment of knee osteoarthritis[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2021, 11(06): 365-371.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhxbygxbzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.2095-1221.2021.06.007

https://zhxbygxbzz.cma-cmc.com.cn/EN/Y2021/V11/I06/365

Figures/Tables 5

References 46

1	Redler LH, Caldwell JM, Schulz BM, et al. Management of articular cartilage defects of the knee[J]. Phys Sportsmed, 2012, 40(1):20-35.
2	Makris EA, Gomoll AH, Malizos KN, et al. Repair and tissue engineering techniques for articular cartilage[J]. Nat Rev Rheumatol, 2015, 11(1):21-34.
3	Lubis AM, Lubis VK. Adult bone marrow stem cells in cartilage therapy[J]. Acta Med Indones, 2012, 44(1):62-68.
4	Friedenstein AJ, Piatetzky-Shapiro II, Petrakova KV. Osteogenesis in transplants of bone marrow cells[J]. J Embryol Exp Morphol, 1966, 16(3):381-390.
5	Caplan AI. Mesenchymal stem cells[J]. J Orthop Res, 1991, 9(5):641-650.
6	Chen FH, Tuan RS. Mesenchymal stem cells in arthritic diseases[J]. Arthritis Res Ther, 2008,10(5):223.
7	Maumus M, Jorgensen C, Noel D. Mesenchymal stem cells in regenerative medicine applied to rheumatic diseases: role of secretome and exosomes[J]. Biochimie, 2013, 95(12):2229-2234.
8	Glenn JD, Whartenby KA. Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy[J]. World J Stem Cells, 2014, 6(5):526-539.
9	Lazarus HM, Haynesworth SE, Gerson SL, et al. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use[J]. Bone Marrow Transplant, 1995, 16(4):557-564.
10	杨振，李浩，付力伟, 等. 膝关节内干细胞/祖细胞在软骨再生中作用研究进展[J]. 中华细胞与干细胞杂志(电子版), 2021, 11(1):51-56.
11	Wakitani S, Goto T, Pineda SJ, et al. Mesenchymal cell-based repair of large, full-thickness defects of articular cartilage[J]. J Bone Joint Surg Am, 1994, 76(4):579-592.
12	Murphy JM, Fink DJ, Hunziker EB, et al. Stem cell therapy in a caprine model of osteoarthritis[J]. Arthritis Rheum, 2003, 48(12):3464-3474.
13	Centeno CJ, Busse D, Kisiday J, et al. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells[J]. Pain physician, 2008, 11(3):343-353.
14	Garay-Mendoza D, Villarreal-Martinez L, Garza-Bedolla A, et al. The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis[J]. Int J Rheum Dis, 2018, 21(1):140-147.
15	Al-Najar M, Khalil H, Al-Ajlouni J, et al. Intra-articular injection of expanded autologous bone marrow mesenchymal cells in moderate and severe knee osteoarthritis is safe: a phase I/II study[J]. J Orthop Surg Res, 2017,12(1):190.
16	Bastos R, Mathias M, Andrade R, et al. Intra-articular injection of culture-expanded mesenchymal stem cells with or without addition of platelet-rich plasma is effective in decreasing pain and symptoms in knee osteoarthritis: a controlled, double-blind clinical trial[J]. Knee Surg Sports Traumatol Arthrosc, 2020, 28(6):1989-1999.
17	Chahal J, Gomez-Aristizabal A, Shestopaloff K, et al. Bone marrow mesenchymal stromal cell treatment in patients with osteoarthritis results in overall improvement in pain and symptoms and reduces synovial inflammation[J]. Stem Cells Transl Med, 2019, 8(8):746-757.
18	Lamo-Espinosa JM, Blanco JF, Sanchez M, et al. Phase II multicenter randomized controlled clinical trial on the efficacy of intra-articular injection of autologous bone marrow mesenchymal stem cells with platelet rich plasma for the treatment of knee osteoarthritis[J]. J Transl Med, 2020,18(1):356.
19	Bastos R, Mathias M, Andrade R, et al. Intra-articular injections of expanded mesenchymal stem cells with and without addition of platelet-rich plasma are safe and effective for knee osteoarthritis[J]. Knee Surg Sports Traumatol Arthrosc, 2018, 26(11):3342-3350.
20	Centeno C, Sheinkop M, Dodson E, et al. A specific protocol of autologous bone marrow concentrate and platelet products versus exercise therapy for symptomatic knee osteoarthritis: a randomized controlled trial with 2 year follow-up[J]. J Transl Med, 2018,16(1):355.
21	Lamo-Espinosa JM, Mora G, Blanco JF, et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: long-term follow up of a multicenter randomized controlled clinical trial (phase I/II)[J]. J Transl Med, 2018, 16(1):213.
22	Emadedin M, Labibzadeh N, Liastani MG, et al. Intra-articular implantation of autologous bone marrow-derived mesenchymal stromal cells to treat knee osteoarthritis: a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial[J]. Cytotherapy, 2018, 20(10):1238-1246.
23	Jayaram P, Ikpeama U, Rothenberg JB, et al. Bone marrow-derived and adipose-derived mesenchymal stem cell therapy in primary knee osteoarthritis: a narrative review[J]. PM R, 2019, 11(2):177-191.
24	Vega A, Martin-Ferrero MA, Del Canto F, et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial[J]. Transplantation, 2015, 99(8):1681-1690.
25	Gupta PK, Chullikana A, Rengasamy M, et al. Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(R): preclinical and clinical trial in osteoarthritis of the knee joint[J]. Arthritis Res Ther, 2016, 18(1):301.
26	Jo CH, Lee YG, Shin WH, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial[J]. Stem cells, 2014, 32(5):1254-1266.
27	Song Y, Du H, Dai C, et al. Human adipose-derived mesenchymal stem cells for osteoarthritis: a pilot study with long-term follow-up and repeated injections[J]. Regen Med, 2018, 13(3):295-307.
28	Jo CH, Chai JW, Jeong EC, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: A 2-year follow-up study[J]. Am J Sports Med, 2017, 45(12):2774-2783.
29	Freitag J, Bates D, Wickham J, et al. Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: a randomized controlled trial[J]. Regen Med, 2019, 14(3):213-230.
30	Lee WS, Kim HJ, Kim KI, et al. Intra-articular injection of autologous adipose tissue-derived mesenchymal stem cells for the treatment of knee osteoarthritis: a phase IIb, randomized, placebo-controlled clinical trial[J]. Stem Cells Transl Med, 2019, 8(6):504-511.
31	Lu L, Dai C, Zhang Z, et al. Treatment of knee osteoarthritis with intra-articular injection of autologous adipose-derived mesenchymal progenitor cells: a prospective, randomized, double-blind, active-controlled, phase IIb clinical trial[J]. Stem Cell Res Ther, 2019, 10(1):143.
32	Zhao X, Ruan J, Tang H, et al. Multi-compositional MRI evaluation of repair cartilage in knee osteoarthritis with treatment of allogeneic human adipose-derived mesenchymal progenitor cells[J]. Stem Cell Res Ther, 2019, 10(1):308.
33	Kuah D, Sivell S, Longworth T, et al. Safety, tolerability and efficacy of intra-articular Progenza in knee osteoarthritis: a randomized double-blind placebo-controlled single ascending dose study[J]. J Transl Med, 2018, 16(1):49.
34	Lu L, Dai C, Du H, et al. Intra-articular injections of allogeneic human adipose-derived mesenchymal progenitor cells in patients with symptomatic bilateral knee osteoarthritis: a Phase I pilot study[J]. Regen Med, 2020, 15(5):1625-1636.
35	Park YB, Ha CW, Lee CH, et al. Cartilage regeneration in osteoarthritic patients by a composite of allogeneic umbilical cord blood-derived mesenchymal stem cells and hyaluronate hydrogel: results from a clinical trial for safety and proof-of-concept with 7 years of extended follow-up[J]. Stem Cells Transl Med, 2017, 6(2):613-621.
36	Matas J, Orrego M, Amenabar D, et al. Umbilical cord-derived mesenchymal stromal Cells (MSCs) for knee osteoarthritis: repeated MSC dosing is superior to a single MSC dose and to hyaluronic acid in a controlled randomized phase I/II trial[J]. Stem Cells Transl Med, 2019, 8(3):215-224.
37	韩建，殷振华，张亚军,等. 人自体脂肪间充质干细胞治疗骨关节炎的临床研究[J]. 实用骨科杂志, 2017, 23(3):235-239.
38	哈承志，李伟，任少达, 等. 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(5):644-652.
39	杨孝兵，蒋峰，张帆, 等. 脐带间充质干细胞治疗严重膝骨关节炎的对照研究[J]. 中国临床药理学与治疗学, 2017, 22(3):305-311.
40	程文丹，徐生林，吴小三,等. 自体骨髓间充质干细胞复合富血小板血浆治疗早期膝关节骨关节炎疗效观察[J]. 中华全科医学, 2019, 17(10):1652-1655.
41	Mahmoudian-Sani MR, Mehri-Ghahfarrokhi A, Hashemzadeh-Chaleshtori M, et al. Comparison of three types of mesenchymal stem cells (bone marrow, adipose tissue, and umbilical cord-derived) as potential sources for inner ear regeneration[J]. Int Tinnitus J, 2017, 21(2):122-127.
42	Heo JS, Choi Y, Kim HS, et al. Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue[J]. Int J Mol Med, 2016, 37(1):115-125.
43	Stanko P, Kaiserova K, Altanerova V, et al. Comparison of human mesenchymal stem cells derived from dental pulp, bone marrow, adipose tissue, and umbilical cord tissue by gene expression[J]. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 2014, 158(3):373-377.
44	Barry F. MSC therapy for osteoarthritis: an unfinished story[J]. J Orthop Res, 2019, 37(6):1229-1235.
45	Liu L, Ho C. Mesenchymal stem cell preparation and transfection-free ferumoxytol labeling for MRI cell tracking[J]. Curr Protoc Stem Cell Biol, 2017, 43:2B.7.1-2B.7.14. doi: 10.1002/cpsc.38.
46	Okano H, Sipp D. New trends in cellular therapy[J]. Development, 2020, 147(18):dev192567. doi: 10.1242/dev.192567.

细胞来源	入组人数	分组方式及使用细胞量	随访期	评估方式	研究结果	参考文献
自体骨髓	61	10 mL骨髓浓缩液	1周，1个月，6个月	X光片，VAS评分，WOMAC评分	VAS↓，WOMAC↓	14
自体骨髓	13	2次30.5×10⁶ MSCs，间隔1个月	1/7/14/28/60天，6/12/18/24个月	KOOS评分，MRI影像	KOOS↑，软骨增厚	15
自体骨髓	47	4×10⁷ MSCs；4×10⁷ MSCs+10 mLPRP	1/2/3/6/9/12个月	KOOS评分，ROM评分，关节腔液细胞因子检测	KOOS↑，ROM↑，IL-10↑	16
自体骨髓	12	低剂量1×10⁶ MSCs；中剂量1×10⁷ MSCs；高剂量5×10⁷ MSCs	2天，1/2/6周，3/6/12/24个月	KOOS评分，WOMAC评分，MRI影像	KOOS↑，WOMAC↓；低剂量组MRI观察到软骨修复	17
自体骨髓	60	第1周：10×10⁷ MSCs+8 mL PRP；之后的2周：每周8 mL PRP	3/6/12个月	VAS评分，WOMAC评分，X光片和MRI影像	VAS↓，WOMAC↓	18
自体骨髓	18	4×10⁷ MSCs，4×10⁷ MSCs+10 mL PRP	1/2/3/6/9/12个月	KOOS评分数据	KOOS↑	19
自体骨髓	48	5 ~ 7 mL骨髓浓缩液+ PRP；注射2 ~ 4 d后再注射3 mL PRP	6周，3/6/12/24个月	KSS评分，VAS评分，SF-12调查表，LEAS评分	KSS↑，VAS↓，SF-12改善，LEAS改善	20
自体骨髓	30	玻璃酸钠+10×10⁶ MSCs；玻璃酸钠+100×10⁶ MSCs	3/6/12个月，4年	VAS评分，WOMAC评分	VAS↓，WOMAC↓	21
自体骨髓	43	4×10⁷ MSCs	1周，3/6个月	VAS评分，WOMAC评分	VAS↓，WOMAC↓	22

细胞来源	入组人数	分组方式及使用细胞量	随访期	评估方式	研究结果	参考文献
自体骨髓	61	10 mL骨髓浓缩液	1周，1个月，6个月	X光片，VAS评分，WOMAC评分	VAS↓，WOMAC↓	14
自体骨髓	13	2次30.5×10⁶ MSCs，间隔1个月	1/7/14/28/60天，6/12/18/24个月	KOOS评分，MRI影像	KOOS↑，软骨增厚	15
自体骨髓	47	4×10⁷ MSCs；4×10⁷ MSCs+10 mLPRP	1/2/3/6/9/12个月	KOOS评分，ROM评分，关节腔液细胞因子检测	KOOS↑，ROM↑，IL-10↑	16
自体骨髓	12	低剂量1×10⁶ MSCs；中剂量1×10⁷ MSCs；高剂量5×10⁷ MSCs	2天，1/2/6周，3/6/12/24个月	KOOS评分，WOMAC评分，MRI影像	KOOS↑，WOMAC↓；低剂量组MRI观察到软骨修复	17
自体骨髓	60	第1周：10×10⁷ MSCs+8 mL PRP；之后的2周：每周8 mL PRP	3/6/12个月	VAS评分，WOMAC评分，X光片和MRI影像	VAS↓，WOMAC↓	18
自体骨髓	18	4×10⁷ MSCs，4×10⁷ MSCs+10 mL PRP	1/2/3/6/9/12个月	KOOS评分数据	KOOS↑	19
自体骨髓	48	5 ~ 7 mL骨髓浓缩液+ PRP；注射2 ~ 4 d后再注射3 mL PRP	6周，3/6/12/24个月	KSS评分，VAS评分，SF-12调查表，LEAS评分	KSS↑，VAS↓，SF-12改善，LEAS改善	20
自体骨髓	30	玻璃酸钠+10×10⁶ MSCs；玻璃酸钠+100×10⁶ MSCs	3/6/12个月，4年	VAS评分，WOMAC评分	VAS↓，WOMAC↓	21
自体骨髓	43	4×10⁷ MSCs	1周，3/6个月	VAS评分，WOMAC评分	VAS↓，WOMAC↓	22

细胞来源	入组人数	分组方式及使用细胞量	随访期	评估方式	研究结果	参考文献
自体脂肪	18	低剂量1×10⁷个MSCs 中剂量2×10⁷个MSCs 高剂量5×10⁷个MSCs	12/24/48/96周	WOMAC评分，SF-36调查表，NRS-11量表	高剂量组WOMAC↓，SF-36和NRS-11改善	27
自体脂肪	18	低剂量1×10⁷个MSCs 中剂量5×10⁷个MSCs 高剂量10×10⁷个MSCs	1/2/3/6个月，1/2年	WOMAC评分，KSS评分，KOOS评分，VAS评分，MRI影像	高剂量组所有评价指标改善	28
自体脂肪	30	1×10⁸个MSCs，单次注射 1×10⁸个MSCs，两次注射，间隔6个月 4×10⁶个MSC，五次注射，基线/1/2/3/6个月	1/3/6/12个月	NPRS评分，KOOS评分，WOMAC评分，MRI影像	两个剂量组所有评分改善，MRI影响观察到疾病缓解	29
自体脂肪	24	1×10⁸个MSCs	6个月	WOMAC评分，MRI影像	WOMAC↓；实验组软骨损伤无变化，对照组软骨损伤加重	30
自体脂肪	53	2次5×10⁷个MSCs，间隔3周	6/12/24个月	VAS评分，WOMAC评分，SF-36评分，MRI影像	WOMAC↓；实验组软骨体积增加	31
异体脂肪	18	低剂量1×10⁷个MSCs 中剂量2×10⁷个MSCs 高剂量5×10⁷个MSCs	1/3/4/8/12/24/36/48周	多模态磁共振成像；WOMAC评分；SF-36调查表	多模态MRI所有序列中改善；WOMAC↓；SF-36改善	32
异体脂肪	20	低剂量3.9×10⁶个MSCs高剂量6.7×10⁶个MSCs	第7/28天，3/6/9/12个月	VAS评分，WOMAC评分，MRI影像	VAS↓，WOMAC↓	33
异体脂肪	22	低剂量1×10⁷个MSCs 中剂量2×10⁷个MSCs 高剂量5×10⁷个MSCs 在第0周和第3周分别接受1次注射	12/24/48周	VAS评分，WOMAC评分，SF-36评分，软骨体积MRI	所有剂量组量表评分均改善，低剂量组改善较明显；低剂量组软骨体积轻微改善	34

细胞来源	入组人数	分组方式及使用细胞量	随访期	评估方式	研究结果	参考文献
自体脂肪	18	低剂量1×10⁷个MSCs 中剂量2×10⁷个MSCs 高剂量5×10⁷个MSCs	12/24/48/96周	WOMAC评分，SF-36调查表，NRS-11量表	高剂量组WOMAC↓，SF-36和NRS-11改善	27
自体脂肪	18	低剂量1×10⁷个MSCs 中剂量5×10⁷个MSCs 高剂量10×10⁷个MSCs	1/2/3/6个月，1/2年	WOMAC评分，KSS评分，KOOS评分，VAS评分，MRI影像	高剂量组所有评价指标改善	28
自体脂肪	30	1×10⁸个MSCs，单次注射 1×10⁸个MSCs，两次注射，间隔6个月 4×10⁶个MSC，五次注射，基线/1/2/3/6个月	1/3/6/12个月	NPRS评分，KOOS评分，WOMAC评分，MRI影像	两个剂量组所有评分改善，MRI影响观察到疾病缓解	29
自体脂肪	24	1×10⁸个MSCs	6个月	WOMAC评分，MRI影像	WOMAC↓；实验组软骨损伤无变化，对照组软骨损伤加重	30
自体脂肪	53	2次5×10⁷个MSCs，间隔3周	6/12/24个月	VAS评分，WOMAC评分，SF-36评分，MRI影像	WOMAC↓；实验组软骨体积增加	31
异体脂肪	18	低剂量1×10⁷个MSCs 中剂量2×10⁷个MSCs 高剂量5×10⁷个MSCs	1/3/4/8/12/24/36/48周	多模态磁共振成像；WOMAC评分；SF-36调查表	多模态MRI所有序列中改善；WOMAC↓；SF-36改善	32
异体脂肪	20	低剂量3.9×10⁶个MSCs高剂量6.7×10⁶个MSCs	第7/28天，3/6/9/12个月	VAS评分，WOMAC评分，MRI影像	VAS↓，WOMAC↓	33
异体脂肪	22	低剂量1×10⁷个MSCs 中剂量2×10⁷个MSCs 高剂量5×10⁷个MSCs 在第0周和第3周分别接受1次注射	12/24/48周	VAS评分，WOMAC评分，SF-36评分，软骨体积MRI	所有剂量组量表评分均改善，低剂量组改善较明显；低剂量组软骨体积轻微改善	34

细胞来源	入组人数	分组及细胞量	随访期	评估方式	研究结果	参考文献
异体脐带	7	0.5×10⁷/mL细胞密度，500 μL/cm²软骨损伤面积	12/24周，1/3/7年	VAS评分，IKDC评分，MRI影像	第6个月时各评分达到最优改善；第3年时观察到软骨修复；7年观察期无不良反应	35
异体脐带	29	组1：1次2×10⁷ MSCs 组2：2次2×10⁷ MSCs，间隔6个月	1/4/8/12/24/36/52周	WOMAC评分，VAS评分，SF-36调查表，MRI影像	实验组2各评分明显改善，但两组MRI影像显示上并无明显区别	36

Please choose a citation manager

Content to export