Application of mesenchymal stem cell therapy for the treatment of osteoarthritis of the knee: A concise review

Table 1 Summary of mesenchymal stem cell preclinical trials in osteoarthritis animal models from 2015 to 2018

Animal models (osteoarthritis)	MSC type	Interventions	Results	Ref.
Sheep	AD-MSCs	AD-MSCs/HA vs HA	µCT, MRI and immunohistochemistry: AD-MSCs/HA > HA	Lv et al[34], 2018
Sheep	Allogeneic AD-MSCs	AD-MSCs/HA vs HA	MRI and macroscopy examinations: AD-MSCs/HA > HA	Feng et al[35], 2017
Rabbits	BMSCs	BMSCs/HA vs PRP vs PRP/HA	Histological scores and immunohistochemistry: BMSCs/HA > PRP/HA > PRP	Desando et al[36], 2017
Rabbits	Allogeneic BMSCs	BMSCs/HA vs HA	Histological scores and cartilage content: BMSCs/HA > HA	Chiang et al[37], 2016
Dogs	AD-MSCs	AD-MSCs/PRP vs PRP	Focal compressive strength: AD-MSCs/PRP > PRP function and pain: AD-MSCs/PRP > PRP	Yun et al[38], 2016
Rabbits	AD-MSCs	AD-MSCs/PRP vs PRP	Macroscopic and histological examinations: AD-MSCs/PRP > PRP	Hermeto et al[39], 2016

OA: Osteoarthritis; AD-MSCs: Adipose-derived mesenchymal stem cells; HA: Hyaluronic acid; MRI: Magnetic resonance imaging; PRP: Platelet-rich plasma; BMSCs: Bone marrow-derived mesenchymal stem cells.

Table 2 Summary of mesenchymal stem cells/platelet-rich plasma clinical trials in osteoarthritis patients from 2012 to 2018

Defect type	MSC type	Delivery system	Type of study	Results	Ref.
OA	AD-MSC	MSCs/PRP	Case series (n = 21); Final follow-up: 6 mo	Significant positive changes at MRI	Bui et al[55], 2014
OA	AD-MSC	MSCs/PRP	Case series (n = 18); Final follow-up: 24.3 mo	Clinical improvement; Function and pain improvement at 24.3 mo	Koh et al[52], 2013
OA	AD-MSC	MSCs/PRP	Case series (n = 30); Final follow-up: 24 mo	Reducing pain and improving function in patients with knee OA	Koh et al[56], 2012
OA	AD-MSC	MSCs/PRP	Case series (n = 21); Final follow-up: 24 mo	Function and pain improvement as compared with PRP only	Koh et al[57], 2014
OA	Autologous SVF	SVF/PRP	Case series (n = 21); Final follow-up: 24 mo	All patients’ scores of pain improved to > 96; and quality of life scores to > 93	Gibbs et al[58], 2015
OA	Autologous SVF	SVF/PRP	Case series (n = 10); Final follow-up: 24 mo	Cartilage thickness improvement	Bansal et al[59], 2017

OA: Osteoarthritis; AD-MSCs: Adipose-derived mesenchymal stem cells; MRI: Magnetic resonance imaging; PRP: Platelet-rich plasma; SVF: Vascular stroma of adipose tissue.

Table 3 Summary of intra-articular injection of expanded bone marrow-derived mesenchymal stem cells in knee osteoarthritis treatment (2015-2018)

Cell type	Type of study	Experimental design	Cell dosage	Measurement	Results	Ref.
Autologous	Case series (n = 61); Final follow up: 6 mo	Phase I/II study	Not mentioned	VAS, WOMAC and X-ray	Significantly reductions in knee pain and increased quality of life at 6 mo follow-up	Garay-Mendoza et al[68], 2018
Autologous	Case series (n = 13); Final follow up: 24 mo	Phase I/II study	Intra-articular injection of 30.5 × 106 MSCs	MRI and KOOS	After intra-articular injection with BM-MSCs had significantly improved the KOOS and knee cartilage thickness	Al-Najar et al[69], 2017
Allogeneic	Case series (n = 60); Final follow up: 24 mo	Double-blind, multicentric, placebo-controlled, phase II study	Four dose levels were studied in this trial: 25 × 106, 50 × 106, 75 × 106, and 150 × 106	VAS, ICOAP and WOMAC	A 25 × 106 cell dose may be the most effective among the doses; WOMAC, ICOAP, and VAS scores decreased by the time of the final follow-up period	Gupta et al[70], 2016
Autologous	Case series (n = 30); Final follow up: 12 mo	Double-blind, multicentric, phase I/II study	Two dose levels were studied in this trial: 10 × 106 and 100 × 106	VAS, WOMAC, X-ray and MRI	A clinical and functional improvement of knee OA by the injection of 100 × 106 cell dose; Improvement of pain and knee function of OA patients at 12 mo follow-up	Lamo-Espinosa et al[71], 2016
Autologous	Case series (n = 4); Final follow up: 60 mo	Phase I study	Intra-articular injection of 8-9 ×  106 MSCs	Walking time, X-ray and VAS	Earlier transplantation may give better results in long-term follow-up	Soler et al[72], 2016
Allogeneic	Case series (n = 30); Final follow up: 12 mo	Multicentric, phase I/II study	Intra-articular injection of 40 × 106 MSCs	VAS, WOMAC, and LEQUESNE; MRI	Significantly improves cartilage quality and provides pain relief	Vega et al[73], 2015
Autologous	Case series (n = 30); Final follow up: 30 mo	Not mentioned	Intra-articular injection of 0.5 × 106 MSCs	Walking distance, VAS, WOMAC and MRI	Significantly improves cartilage quality and knee function, and reduces pain level	Emadedin et al[74], 2015
Autologous	Case series (n = 4); Final follow up: 60 mo	Phase I study,open label	Intra-articular injection of 8 × 106 MSCs	VAS, Knee motion, Range, X-ray	Earlier transplantation may give better results in long-term follow-up	Davatch et al[75], 2016

VAS: Visual Analogue Scale/Score; WOMAC: The Western Ontario and McMaster Universities; MRI: Magnetic resonance imaging; MSCs: Mesenchymal stem cells; KOOS: Knee Injury and Osteoarthritis Outcome; BM-MSCs: Bone marrow-derived mesenchymal stem cells; ICOAP: The Intermittent and Constant Osteoarthritis Pain Score; OA: Osteoarthritis.

Table 4 Summary of intra-articular injection of expanded umbilical cord-derived mesenchymal stem cells in knee osteoarthritis treatment (2015-2018)

Cell type	Type of study	Experimental design	Cell dosage	Measurement	Results	Ref.
Allogeneic	Case series (n = 7); Final follow-up: 60 mo	Open-label, single-arm, single-center, phase I/II study	A dose of 500 µL/cm2 of the defect area with a cell concentration of 0.5 × 107 MSCs per milliliter	ICRS, VAS, IKDC and MRI	Improvements in pain and knee function at 6 mo follow-up; Without significant deterioration over 7 yr of follow-up; Efficacy and safety	Park et al[66], 2017
Allogeneic	Case series (n = 36); Final follow up: 12 mo	Not mentioned	Intra-articular injection of (2-3) × 107 MSCs	Lysholm, WOMAC and SF-36 scale score	Improvement of the joint function and quality of life	Wang et al[76], 2016
Allogeneic	Case series (n = 40); Final follow up: 12 mo	randomized, triple-blind trial, phase I/II trial	Intra-articular injection of 20 × 106 (single-dose and repeated doses) MSCs	OARSI, WOMAC, VAS and SF-36 score	Efficacy and safety; Repeated injections of UC-MSCs had lower scores than others at 12 mo; Improvement of pain and knee function of OA patients at 12 mo follow-up	Matas et al[77], 2018

ICRS: International Cartilage Repair Society; VAS: Visual Analogue Scale/Score; IKDC: The International Knee Documentation Committee; MSCs: Mesenchymal stem cells; WOMAC: The Western Ontario and McMaster Universities; OARSI: Osteoarthritis Research Society International; SF-36: The MOS item short from health survey; UC-MSCs: Umbilical cord-derived mesenchymal stem cells; OA: Osteoarthritis.

Table 5 Summary of intra-articular injection of expanded adipose-derived mesenchymal stem cells in knee osteoarthritis treatment (2015-2018)

Cell type	Type of study	Experimental design	Cell dosage	Measurement	Results	Ref.
Autologous	Case series (n = 18); Final follow-up: 24 mo	Randomized and Double-blinded, A phase I/II study	Three dose groups: The low-dose (1 × 107), mid-dose (2 × 107) and high-dose group (5 × 107) cells	WOMAC, SF-36 and NRS-11	The dosage of 5 × 107 MSCs exhibited the highest improvement in pain, function and cartilage volume of the knee joint	Song et al[78], 2018
Autologous	Case series (n = 18); Final follow-up: 24 mo	A phase I/II study	Phase I: 10 × 106 (low-dose), 50 × 106 (mid-dose), 100 × 106 (high-dose); Phase II:100 × 106 (high-dose)	VAS, WOMAC and MRI	A 100 × 106 cell dose may be the most effective among the doses	Jo et al[79], 2017
Autologous	Case series (n = 18); Final follow-up: 20 mo	A phase I, bicentric, single-arm, open-label	Three dose levels were studied in this trial: 2 × 106 (low-dose), 10 × 106 (mid-dose) and 50 × 106 (high-dose) cells	WOMAC, VAS, SF-36, KOOS and OARSI	The group of patients injected with 2 × 106 cells exhibited the best response to MSC treatment, which can improve pain and induce structural benefit	Pers et al[80], 2016

WOMAC: The Western Ontario and McMaster Universities; SF-36: The MOS item short from health survey; NRS-11: The 11-point Numerical Rating Scale; MSCs: Mesenchymal stem cells; VAS: Visual Analogue Scale/Score; MRI: Magnetic resonance imaging; OARSI: Osteoarthritis Research Society International; KOOS: Knee Injury and Osteoarthritis Outcome.