Mesenchymal stem cells for enhancing biological healing after meniscal injuries

Table 1 Summary of recent preclinical and clinical studies regarding intra-articular mesenchymal stem cell injection for meniscus healing

Ref.	Cell source	Preclinical/clinical	Model	Results
Ishimura et al[147], 1997	BM-MSCs	Preclinical	Rabbit	Meniscal defects in the fibrin glue group (F group) and fibrin glue with MSC group (M group) were significantly smaller than those in the controls. Histological study showed earlier healing in the M group than F group
Murphy et al[156], 2003	BM-MSCs	Preclinical	Goat	At 6 wk, marked regeneration was identified with implanted cells detected in the newly formed tissue in treated joints. Reduced cartilage degeneration, osteophytic remodeling, and subchondral sclerosis were found in the treated joints than the controls
Abdel-Hamid et al[157], 2005	BM-MSCs	Preclinical	Canine	After 12 wk, angiogenesis, chondrogenesis, immune cell infiltrate, and proliferation of the fibroblasts were significantly higher in the treated group
Agung et al[151], 2006	BM-MSCs	Preclinical	Rat	At 4 weeks, green fluorescent protein (GFP) (+) cells were identified in injured ACL in all 8 knees in the 1 × 106 MSC group. In the 1 × 107 MSC group, GFP (+) cells were observed in the injured ACL in all 8 knees and in the injured meniscus in 6 of 8 knees. Extracellular matrix stained by toluidine blue was visible around GFP (+) cells indicating tissue regeneration
Mizuno et al[152], 2008	S-MSCs	Preclinical	Rat	One day after injection, the meniscal defect was filled with the cells. The MSC group expressed type II collagen, exhibited characteristics of chondrocytes at 8 wk, and still observed at 12 wk. Histological score improved within 12 wk without statistical difference
Centeno et al[161], 2008	BM-MSCs	Clinical	Human	At 3 mo, MRI analysis demonstrated an increased meniscus volume. Modified VAS scores decreased from 3.33 to 0.13
Horie et al[153], 2009	S-MSCs	Preclinical	Rat	After 12 wk, regenerated menisci were LacZ (+), produced type II collagen, and showed meniscal features on electron microscopy. LacZ gene derived from MSCs was not detected in other distant organs
Dutton et al[154], 2010	BM-MSCs	Preclinical	Pig	At 8 wk, gross examination of group 1 (control) showed no healing. In group 2 (suture with fibrin glue), no healing was found in 12 knees and incomplete healing in 7 knees. Group 3 (suture with MSCs) had complete healing in 21 knees, incomplete healing in 5 knees, and no healing in 2 knees (P < 0.001). Biomechanical study showed a significant improvement in group 3 compared with group 1 and 2. Microscopic analysis showed fluorescence in group 3
Ruiz-Ibán et al[150], 2011	A-MSCs	Preclinical	Rabbit	At 12 wk, intralesional injection of A-MSCs increased the healing rate (P = 0.002). Histologic analysis showed well-formed meniscal fibrocartilage with cells derived from the MSCs
Al Faqeh et al[158], 2012	BM-MSCs	Preclinical	Sheep	At 6 wk, injection of BM-MSCs either chondrogenically induced or not, could retard the OA progression. The induced cells showed better meniscal regeneration
Horie et al[148], 2012	S-MSCs	Preclinical	Rabbit	Quantity of regenerated tissue in MSC group was greater at all time points, reaching significance at 4 and 12 weeks (P < 0.05). Tissue quality scores were superior in MSC group than controls at all end points, achieving significance at 12 and 24 wk. MSCs were observed in the regenerated tissue with differentiation up to 24 wk
Hatsushika et al[149], 2013	S-MSCs	Preclinical	Rabbit	Meniscus size in MSC group was larger than in control group at 1 and 3 mo. Histological score was better in MSC group up to 6 mo. The femoral condyle cartilage looked intact in MSC group at 6 mo. Histologically, cartilage and subchondral bone were better preserved in MSC group
Caminal et al[159], 2014	BM-MSCs	Preclinical	Sheep	At 12 mo, evidence of meniscus regeneration was case-dependent. However, statistically significant improvement was observed in specific macroscopic and histological parameters
Hatsushika et al[155], 2014	S-MSCs	Preclinical	Porcine	Meniscus regeneration was significantly better in MSC group on histological and MRI analyses up to 16 wk. Grossly, the meniscal defect was filled with synovial tissue at 2 wk. Articular cartilage and subchondral bone were also significantly better preserved in MSC group
Ferris et al[160], 2014	BM-MSCs	Preclinical	Horse	At 24 mo follow-up, 43% of horses returned to previous work level, 33% returned to work, and 24% failed to return. In horses with meniscal damage (n = 24) a higher percentage (75%) returned to some level of work compared with those in previous reports (63%) treated with arthroscopy alone (P = 0.038)
Pak et al[104], 2014	A-MSCs	Clinical	Human	At 3 mo, patient’s symptoms improved and repeated MRI showed almost complete disappearance of the meniscal lesion. Until 18 mo, symptom improvement persisted without any serious side effects
Okuno et al[103], 2014	S-MSCs	Preclinical	Rat	At 4 wk, syngeneic and minor mismatched transplantation of MSCs promoted meniscus regeneration better than major mismatched transplantation
Vangsness et al[95], 2014	BM-MSCs	Clinical	Human	No important safety issues were identified. Significantly increased meniscal volume was determined by quantitative MRI in MSC group at 12 mo (P = 0.022). In patients with OA, MSC group experienced a significant reduction in pain than control group on the basis of VAS assessments
Nakagawa et al[92], 2015	S-MSCs	Preclinical	Microminipig	At 12 wk, meniscal healing was significantly better in MSC group macroscopically, histologically and by T1rho mapping analysis. Transmission electron microscopy showed the meniscus lesion occupied by dense collagen fibrils in MSC group. Biomechanical test revealed higher tensile strength in MSC group than in control group. Synovial tissue covered better the meniscus lesion in MSC group at 2 and 4 wk. Labeled MSCs were detected in the meniscus lesion by MRI at 2 wk
Qi et al[105], 2016	A-MSCs	Preclinical	Rabbit	At 12 wk, hypointense artifacts caused by SPIO (+) cells in the meniscus were detected by MRI. Histological analysis revealed that the healed meniscus was similar to native tissue in treated group. Collagen-rich matrix integrated well with its host meniscus. Although degenerative changes occurred in all groups, injection of MSCs alleviated these degenerative changes
Sekiya et al[98], 2019	S-MSCs	Clinical	Human	Lysholm knee scores were significantly higher at 1 yr than before the treatment, and maintained at 2 yr. KOOS for daily living pain, and sports and recreational activities increased significantly at 2 yr. NRS scores continually increased and showed significant improvement at 2 yr, 3D MRI showed indistinguishable healing at the meniscal lesion
Onoi et al[99], 2019	A-MSCs	Clinical	Human	No serious adverse events were reported during 6-mo follow-up. Pain and function were significantly improved in treated knees up to 6 mo. At 6 mo, second-look arthroscopy showed repaired meniscus
Ozeki et al[81], 2021	S-MSCs	Preclinical	Microminipig	Proteoglycan content stained with safranin-o disappeared 1 wk after treatment in both MSC and control groups, but increased at 8 wk only in MSC group. At 8 wk, histological scores were significantly higher and T2 values were significantly closer to those of normal meniscus in MSC group

BM-MSCs: Bone marrow-derived mesenchymal stem cells; MSC: Mesenchymal stem cell; GFP: Green fluorescent protein; ACL: Anterior cruciate ligament; S-MSCs: Synovium-derived mesenchymal stem cells; MRI: Magnetic resonance imaging; VAS: Visual analog scale; A-MSCs: Adipose-derived mesenchymal stem cells; OA: Osteoarthritis; SPIO: Superparamagnetic iron oxide; KOOS: Knee injury and outcome osteoarthritis score; NRS: Numerical rating scale.