Comparative effectiveness of adipose-derived mesenchymal stromal cells in the management of knee osteoarthritis: A meta-analysis

Table 1 Characteristics of included studies

Sl. No	Ref.	Country	Nature of study	Kellgren Lawrence Grade	Sample size	Treatment/control	Mean age (SD)		Male/female		MSC type	MSC source	Follow-up (mo)
							Treatment group	Control group	Treatment group	Control group
1	Vega et al[23], 2015	Spain	RCT	II, III, IV	30	15/15	56.6 ± 9.24	57.3 ± 9.09	06/09	05/10	BM	Allo	12
2	Vangsness et al[24], 2014	United States	RCT	NR	55	36/19	44.6 ± 9.82	47.8 ± 8	25/11	13/06	BM	Allo	24
3	Garay-Mendoza et al[25], 2018	Mexico	RCT	NR	61	30/31	55.57 ± 12.02	59.32 ± 10.85	07/23	09/22	BM	Auto	6
4	Kuah et al[26], 2018	Australia	RCT	I, II, III	20	16/4	50.8 ± 7.29	55.0 ± 10.42	11/05	01/03	AD	Allo	12
5	Estrada et al[22], 2020	Argentina	RCT	I, II, III	89	60/29	61 ± 12	61 ± 12	NR	NR	BM / AD	Auto	12
6	Freitag et al[27], 2019	Australia	RCT	II, III	30	20/10	54.6 ± 6.3	51.5 ± 6.1	11/09	01/09	AD	Auto	12
7	Ruane et al[41], 2021	United States	RCT	I, II, III	32	17/15	58.06 ± 9.14	58.6 ± 8.05	09/08	10/05	BM	Auto	12
8	Lamo-Espinosa et al[28], 2016	Spain	RCT	II, III, IV	30	20/10	65.9	60.3	12/08	07/03	BM	Auto	12
9	Garza et al[29], 2020	United States	RCT	II, III	39	26/13	60.5 ± 7.9	57.1 ± 9.1	15/11	7/6	AD	Auto	12
10	Wong et al[30], 2013	Singapore	RCT	NR	56	28/28	53	49	15/13	14/14	BM	Auto	24
11	Lu et al[31], 2019	China	RCT	I, II, III	53	27/26	55.03 ± 9.19	59.64 ± 5.97	03/24	03/23	AD	Auto	12
12	Lv et al[42], 2015	Huang	RCT	I, II	80	40/40	55.9 ± 8.1	55.1 ± 6.8	14/26	13/27	BM	Auto	12
13	Emadedin et al[32], 2018	Iran	RCT	II, III, IV	43	19/24	51.7 ± 9.2	54.7 ± 5.3	12/07	15/09	BM	Auto	6
14	Gupta et al[33], 2016	India	RCT	II, III	60	40/20	58.10 ± 8.23	54.90 ± 8.27	12/28	4/16	BM	Allo	12
15	Bastos et al[34], 2020	Brazil	RCT	I, II, III, IV	47	30/17	55.7 ± 7.8	55.9 ± 13.4	15/15	09/08	BM	Auto	12
16	Wakitani et al[35], 2002	Japan		I, II	24	12/12	NR	NR	NR	NR	BM	Auto	16
17	Tran et al[36], 2019	Taiwan	RCT	II, III	33	15/18	58.2 ± 5.70	59.0 ± 6.04	03/12	05/13	AD	Auto	24
18	Lee et al[37], 2019	South Korea	RCT	II, III, IV	24	12/12	62.2 ± 6.5	63.2 ± 4.2	03/09	03/09	AD	Auto	6
19	Koh et al[38], 2012	South Korea	RCT	IV	50	25/25	54.2 ± 9.3	54.4 ± 11.3	08/17	08/17	AD	Auto	16
20	Koh et al[39], 2014	South Korea	RCT	I, II, III	44	23/21	52.3 ± 4.9	54.2 ± 2.9	06/17	05/16	AD	Auto	24
21	Hong et al[40], 2019	China	RCT	II, III	32	16/16	51 ± 5.95	53 ± 10.97	03/13	03/13	AD	Auto	12

AD: Adipose derived; Allo: Allogenic; Auto: Autologous; BM: Bone marrow; MSC: Mesenchymal stem cell; NR: Not reported; RCT: Randomized controlled trial; SD: Standard deviation.

Table 2 Stem cell transplantation protocol of the included studies

Ref.	MSC type	MSC source	MSC preparation	MSC count (107 cells)	Treatment group intervention	Control group intervention	Outcome measures
Vega et al[23], 2015	BM	Allo	CE-BMMSC	4	sIA injection of MSC	sIA Injection of 60 mg HA	VAS, WOMAC
Vangsness et al[24], 2014	BM	Allo	CE-BMMSC	5/15	sIA injection of MSC + 20 mg HA	sIA Injection of 20 mg HA	VAS, Lysholm Score
Garay-Mendoza et al[25], 2018	BM	Auto	BMC	NA	600 μg/d G-CSF for 3 consecutive days before the procedure + sIA injection of MSC	Oral acetaminophen, 500 mg every 8 h for 6 mo	VAS, WOMAC
Kuah et al[26], 2018	AD	Allo	CE-ADMSC	0.39-0.67	sIA injection of MSC	Placebo sIA injection of cell culture media and cryopreservative	VAS, WOMAC, MRI assessment
Estrada et al[22], 2020	AD	Auto	BMC	NA	sIA injection of BM concentrate	sIA injection of PRP	IKDC, Lysholm Score, KOOS
Estrada et al[22], 2020	BM	Auto	SVF	NA	sIA injection of lipoaspirate	sIA injection of PRP
Freitag et al[27], 2019	AD	Auto	CE-ADMSC	10	sIA injection of MSC ± 2nd injection at 6 mo	Conservative management	VAS, WOMAC, KOOS, MRI assessment
Ruane et al[41], 2021	BM	Auto	BMC	NA	sIA injection of BM concentrate + PRP	Gel-One® Cross-Linked hyaluronate injection	VAS, KOOS
Lamo-Espinosa et al[28], 2016	BM	Auto	CE-BMMSC	1	sIA injection of MSC + 60 mg HA	sIA injection of 60 mg HA	VAS, WOMAC, MRI assessment
Garza et al[29], 2020	AD	Auto	SVF	NA	sIA injection of MSC	Placebo injection without cells	WOMAC, MRI assessment
Wong et al[30], 2013	BM	Auto	CE-BMMSC	1.46	HTO + microfracture + sIA injection of MSC + 20 mg HA	HTO + microfracture + sIA injection of 20 mg HA	Tegner Score, Lysholm Score
Lu et al[31], 2019	AD	Auto	CE-ADMSC	5	2 IA injection of MSC at 0, 3 wk and sham injection at 1, 2 wk	4 IA injection of 25 mg HA at 0, 1, 2, 3 wk	VAS, WOMAC
Lv et al[42], 2015	BM	Auto	CE-BMMSC	3.82	3 × monthly IA injection of MSC + 20 mg HA	sIA injection of 20 mg HA	Tegner Score, Lysholm Score
Emadedin et al[32], 2018	BM	Auto	CE-BMMSC	4	sIA injection of MSC	Placebo sIA injection of normal saline	VAS, WOMAC
Gupta et al[33], 2016	BM	Allo	CE-BMMSC	2.5-15	sIA injection of MSC + 20 mg HA	Placebo sIA injection of 20 mg HA	VAS, WOMAC, MRI assessment
Bastos et al[34], 2020	BM	Auto	CE-BMMSC	4	sIA injection of MSC in 10 mL of PRP	sIA injection of 4 mg dexamethasone	KOOS, MRI assessment
Wakitani et al[35], 2002	BM	Auto	CE-BMMSC	1	HTO + microfracture + sIA injection of MSC	HTO + microfracture + placebo injection	MRI assessment, HSS knee rating scale
Tran et al[36], 2019	AD	Auto	SVF	NA	Arthroscopic micro fracture + sIA injection of MSC	Arthroscopic micro fracture	WOMAC, MRI assessment
Lee et al[37], 2019	AD	Auto	CE-ADMSC	10	sIA injection of MSC	Placebo injection with normal saline	WOMAC, MRI assessment
Koh et al[38], 2012	AD	Auto	SVF	0.189	Arthroscopic debridement + sIA injection of MSC + PRP	Arthroscopic debridement + PRP	VAS, Tegner Score, Lysholm Score
Koh et al[39], 2014	AD	Auto	CE-ADMSC	0.411	HTO + sIA injection of MSC + PRP	HTO + PRP	VAS, Lysholm Score
Hong et al[40], 2019	AD	Auto	SVF	0.745	sIA injection of MSC	sIA injection of 40 mg HA	VAS, WOMAC, MRI assessment

AD: Adipose derived; Allo: Allogenic; Auto: Autologous; BM: Bone marrow; BMC: Bone marrow concentrate; CE-ADMSC: Culture expanded adipose derived mesenchymal stem cell; CE-BMMSC: Culture expanded bone marrow mesenchymal stem cell; HA: Hyaluronic acid; HSS: Hospital for special surgeries; HTO: High tibial osteotomy; IA: Intra-articular; IKDC: International Knee Documentation Committee; KOOS: Knee Osteoarthritis Outcome Score; PRP: Platelet rich plasma; MRI: Magnetic resonance imaging; MSC: Mesenchymal stem cell; sIA: Single intra-articular; SVF: Stromal vascular fraction; VAS: Visual analog score; WOMAC: Western Ontario Mc-Master Universities Osteoarthritis index.