Review
Copyright ©The Author(s) 2021.
World J Stem Cells. Aug 26, 2021; 13(8): 1005-1029
Published online Aug 26, 2021. doi: 10.4252/wjsc.v13.i8.1005
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], 1997BM-MSCsPreclinicalRabbitMeniscal 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], 2003BM-MSCsPreclinicalGoatAt 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], 2005BM-MSCsPreclinicalCanineAfter 12 wk, angiogenesis, chondrogenesis, immune cell infiltrate, and proliferation of the fibroblasts were significantly higher in the treated group
Agung et al[151], 2006BM-MSCsPreclinicalRatAt 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], 2008S-MSCsPreclinicalRatOne 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], 2008BM-MSCsClinicalHumanAt 3 mo, MRI analysis demonstrated an increased meniscus volume. Modified VAS scores decreased from 3.33 to 0.13
Horie et al[153], 2009S-MSCsPreclinicalRatAfter 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], 2010BM-MSCsPreclinicalPigAt 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], 2011A-MSCsPreclinicalRabbitAt 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], 2012BM-MSCsPreclinicalSheepAt 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], 2012S-MSCsPreclinicalRabbitQuantity 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], 2013S-MSCsPreclinicalRabbitMeniscus 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], 2014BM-MSCsPreclinicalSheepAt 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], 2014S-MSCsPreclinicalPorcineMeniscus 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], 2014BM-MSCsPreclinicalHorseAt 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], 2014A-MSCsClinicalHumanAt 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], 2014S-MSCsPreclinicalRatAt 4 wk, syngeneic and minor mismatched transplantation of MSCs promoted meniscus regeneration better than major mismatched transplantation
Vangsness et al[95], 2014BM-MSCsClinicalHumanNo 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], 2015S-MSCsPreclinicalMicrominipigAt 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], 2016A-MSCsPreclinicalRabbitAt 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], 2019S-MSCsClinicalHumanLysholm 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], 2019A-MSCsClinicalHumanNo 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], 2021S-MSCsPreclinicalMicrominipigProteoglycan 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
Table 2 Summary of recent preclinical and clinical studies regarding tissue engineering using mesenchymal stem cells for meniscus healing
Ref.
Cell source
Preclinical/clinical
Model
Results
Walsh et al[163], 1999BM-MSCs (type I collagen scaffold)PreclinicalRabbitMeniscal defect was left untreated (group 1) or treated with periosteal autograft (group 2), a type I collagen sponge (group 3), or the sponge loaded with MSCs (group 4). In group 4, regenerated tissue was the most abundant. Grossly, transition zone was well healed. Regenerated meniscus established normal appearing tissue. At 24 wk, meniscus-like tissue was predominantly identified with proteoglycan staining on safranin O-fast green
Angele et al[18], 2008BM-MSCs (composite scaffold composed of 70% completely derivatized hyaluronan-ester and 30% gelatin)PreclinicalRabbitAfter 12 wk, pre-cultured implants integrated with the host tissue. 8 of 11 had meniscus-like fibrocartilage, compared with 2 of 11 in controls (P < 0.03). Cross-sectional width of the pre-cultured implant repair tissue was greater than controls (P < 0.004)
Zhang et al[166], 2009BM-MSCs (transfection of human hIGF-1 gene combined with injectable calcium alginate gel)PreclinicalGoatAt 16 wk, in treated group, meniscal defects were filled with regenerated tissue similar to normal meniscal fibrocartilage. Repair tissue was composed of cells embedded within fiber matrix. The proteoglycan content in treated group was higher than those in control groups
Zellner et al[164], 2010BM-MSCs (sponge scaffold manufactured from 70% derivatized hyaluronan-ester and 30% gelatin)PreclinicalRabbitAt 12 wk, implantation of precultured chondrogenic MSC constructs showed fibrocartilage-like repair tissue with only partial integration with native meniscus. Non-precultured MSC group showed development of completely integrated meniscus-like tissue
Hong et al[164], 2011BM-MSCs (matrix gel scaffold)PreclinicalRabbitAt 8 wk, no groups showed the healing response. There was no significant difference in the pathological criteria between treated and control groups
Moriguchi et al[167], 2013S-MSCs [scaffold-free tissue engineered construct (TEC)]PreclinicalMiniature pigAt 6 mo, MSC group showed tissue repair with fibro-cartilaginous tissue and good integration. The ratio of Safranin O positive area was significantly higher in treated group than in control group (P = 0.03). The treated group showed significantly reduced chondral lesions (P = 0.016) and better ICRS scores (P = 0.008)
Zellner et al[78], 2013BM-MSCs (sponge scaffold manufactured from 70% completely derivatized hyaluronan-ester and 30% gelatin)PreclinicalRabbitAt 12 wk, the MSC groups showed fibrocartilage-like repair tissue, and better integration and biomechanical properties were identified especially in the precultured-MSC applied group
Katagiri et al[169], 2013S-MSCs (aggregate of S-MSCs)PreclinicalRatAt 4 wk, the regenerated meniscus was larger and histological findings were closer to the normal meniscus in MSC-aggregate groups than in MSC-suspension group. The effects of MSC-aggregate were still observed at 12 wk. Luminescence intensity remained higher after 3 wk in the MSC-aggregate group
Desando et al[82], 2016BM-MSCs and bone marrow concentrate (BMC) (hyaluronan-based biodegradable polymer)PreclinicalSheepAt 12 wk, BMC group showed a better repair ability in inhibiting OA progression than BM-MSC group. In addition, the BMC group showed the best results in meniscus regeneration
Qi et al[168], 2016BM-MSCs (transplantation of MSCs sheet) PreclinicalRatAt 8 wk, histological analysis revealed that healed meniscus was similar to native tissue in the treated group. Furthermore, predominant collagen-rich matrix bridging the interface was identified and the regenerated meniscus integrated well with surrounding host meniscus
González-Fernández et al[100], 2016BM-MSCs or A-MSCs (collagen repair patch)PreclinicalHorseAt 1 yr, the control group had full-thickness defects. Defects remained in only 1 of the 6 menisci in MSC groups without any differences between A-MSC and BM-MSC groups. Histologically, quantity of regenerated meniscal tissue was better in MSC groups than in controls (P < 0.001)
Moradi et al[165], 2017A-MSCs and articular chondrocyte (AC) (Polyvinyl alcohol/Chitosan (PVA/Ch) scaffoldPreclinicalRabbitAt 7 mo, macroscopic and histologic studies revealed better results in AC/scaffold group followed by AC-A-MSC (co-culture)/scaffold and A-MSC/scaffold groups. Articular cartilages were best preserved in AC/scaffold group. Highest histologic scores were identified in the AC/scaffold group
Kondo et al[93], 2017S-MSCs (aggregateof S-MSCs)PreclinicalMonkeyThe meniscus was larger and the modified Pauli’s histological score was better in treated group at 8 and 16 wk. At 16 wk, Mankin’s score for medial femoral condyle cartilage was better in treated group. T1rho values for regenerated meniscus was closer to the normal meniscus in treated group
Zellner et al[77], 2017BM-MSCs (hyaluronan collagen composite matrix)PreclinicalRabbitAt 3 mo, MSC group showed meniscal defects completely filled with dense repair tissuea. Histologically, regenerated tissue was meniscus-like with typical pericellular meniscal cavities and extensive extracellular matrix. Immunostaining for type II collagen was moderately positive. The repaired tissue showed typically radially orientated collagen fibers. MSC group had significantly increased type II collagen gene expression and production (P < 0.05)
Whitehouse et al[96], 2017BM-MSCs (collagen scaffolds)ClinicalHumanFive patients were treated and there was significant clinical improvement in 3 patients. The 3 patients were asymptomatic at 24 mo without retear in MRI. Two required subsequent meniscectomies at 15 mo
Toratani et al[106], 2017A-MSCs (high-density MSC scaffold-free allograft constructs (HDMACs))PreclinicalRabbitGrossly, tissue healing was significantly greater in treated group at 2, 4, and 8 wk (P = 0.01). Safranin-O staining was positive at 2 wk and increased gradually over time in treated group. Histological scores were significantly higher in treated group at all weeks (P < 0.05)
Koch et al[102], 2018BM-MSCs (polyurethane scaffolds)PreclinicalRabbitAt 12 wk, in both cell-free and MSC groups showed well-integrated and stable meniscus-like repair tissue. But, accelerated healing was notice in MSC group
Olivos-Meza et al[97], 2019Peripheral blood MSCs (polyurethane scaffolds)ClinicalHumanIn tibial T2 mapping, values in MSC group increased slightly at 9 mo but returned to initial values at 12 mo. In control group, decrease from 3 mo to 12 mo was observed. This difference tended to be lower in control group compared with MSC group at 1 yr (P = 0.18). In the femur, a slight increase in MSC group compared with control group was observed (P > 0.05)