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Table 1 Large animal studies assessing mesenchymal stem cell-based treatment of chondral and osteochondral defects

From: Mesenchymal stem cells in the treatment of traumatic articular cartilage defects: a comprehensive review

Scientific publication Animal model Simulated defect characteristics Implanted/injected construct Follow-up period Key findings
Guo et al. (2004) [65] 28 sheep Medial femoral condyle osteochondral defects; cylindrical (8 mm diameter) Implantation of isolated BM-derived MSCs seeded on a TCP scaffold; compared to cell-free scaffolds and empty defects 6 months Macroscopic: smooth, integrated tissue in MSC group. Histologic: proteoglycan and type II collagen consistent with hyaline cartilage in MSC group, compared with fibrocartilage in cell-free group; subchondral osseous regeneration. Biochemical: GAG quantity in MSC group was 89% of native cartilage
Wayne et al. (2005) [66] 10 dogs Medial and lateral femoral condyle osteochondral defects; cylindrical (6 mm diameter) Implantation of isolated BM-derived MSCs suspended in alginate and seeded on a PLA scaffold; precultivated for 3 wk; compared to cell-free scaffolds 1.5 months Macroscopic: improved coverage of defects in MSC group. Histologic: mixture of hyaline and fibrocartilage integrated with surrounding tissue; higher quality tissue in MSC group compared with cell-free group; no mineralization noted within osseous defects. Mechanical: lower resistance to compression than native cartilage
Ando et al. (2007) [67] 9 piglets Medial femoral condyle chondral defects; cylindrical (8.5 mm diameter) Implantation of isolated, allogeneic synovial tissue MSCs derived from piglets and cultured in a three-dimensional scaffold-free TEC; compared to empty defects 6 months Macroscopic: greater defect coverage in TEC group; subchondral erosion in the empty defects. Histologic: smooth, integrated tissue containing proteoglycans and type II collagen in the TEC group; empty defects showed signs of OA; higher ICRS scores in the TEC group. Mechanical: similar viscoelastic properties between TEC and native cartilage
Lee et al. (2007) [68] 27 mini-pigs Medial femoral condyle chondral defects; cylindrical (8.5 mm diameter) Injection of isolated BM-derived MSCs with HA (Synvisc) followed by HA weekly × 2 wk; compared to HA alone 3 months Macroscopic: greater defect coverage in the MSC + HA group. Histologic: hyaline-like cartilage noted in MSC + HA group; minimal defect filling in HA group; improvement in Wakitani histologic score with MSCs
Saw et al. (2009) [69] 15 goats Femoral trochlea chondral defects; cylindrical (4 mm diameter) Injection of BMDC collection with HA (Hyalgan) weekly for 3 wk starting 1 wk after subchondral drilling; compared to drilling with or without HA 6 months Macroscopic: greater defect coverage in the BMDC + HA group. Histologic: HA group had some proteoglycans and type II collagen mixed with type I collagen; BMDC + HA group had superior proteoglycan and type II collagen content; cell morphology was improved in the BMDC + HA group
Zscharnack et al. (2010) [38] 10 sheep Medial femoral condyle osteochondral defects; cylindrical (7 mm diameter) Implantation of isolated BM-derived MSCs in type I (rat) collagen gel either immediately following seeding or after 2 wk of precultivation 6 months Macroscopic: precultivation group produced more homogenous hyaline-like cartilage. Histologic: significantly better O’Driscoll and ICRS scores in the precultivation group compared with non-precultivated group, specifically with respect to surface features, integration, cell distribution, and mineralization. Mechanical: precultivated tissue was firm
Shimomura et al. (2010) [70] 7 pigs, 6 piglets Medial femoral condyle chondral defects; cylindrical (8.5 mm diameter) Implantation of isolated synovial tissue MSCs derived from piglets and cultured in a three-dimensional scaffold-free TEC; compared to empty defects 6 months Macroscopic: greater defect coverage in TEC group. Histologic: good integration of tissue that stained well for proteoglycans in the TEC group versus signs of OA in empty defects; higher ICRS scores in the TEC group. Mechanical: similar properties between TEC and native tissue
Wegener et al. (2010) [71] 9 sheep Medial femoral condyle chondral defects; cylindrical (8 mm diameter) Implantation of BM cells in fibrin glue seeded on a PGA scaffold; secured to subchondral bone by PLGA darts; compared to cell-free scaffolds 3 months Macroscopic: BM-seeded scaffolds had improved regeneration compared with cell-free scaffolds. Histologic: variation noted with fibrous tissue in some and hyaline-like cartilage in other BM cell-seeded scaffolds; O’Driscoll score was similar between cell-free and cell-seeded scaffolds
Marquass et al. (2011) [72] 9 sheep Medial femoral condyle osteochondral defects; cylindrical (7 mm diameter) Implantation of isolated BM-derived MSCs in type I (rat) collagen gel implanted either immediately following seeding or after 2 wk of precultivation; compared to MACI 12 months Macroscopic/histologic: significantly better O’Driscoll and ICRS scores with precultivated MSCs compared with both non-precultivated MSCs and MACI, specifically with respect to surface quality, matrix quality and integration; type II collagen content was superior in precultivated group. MRI: precultivated MSCs were similar to MACI but significantly better than non-precultivated MSCs on the MOCART score
McIlwraith et al. (2011) [73] 10 horses Medial femoral condyle chondral defects (1 cm2) Injection of isolated BM-derived MSCs with HA (Hyvisc) into the knee joint 1 month after MFX; compared to cell-free HA injection and MFX 12 months Macroscopic: greater repair tissue area with MSCs, but no difference in volume. Histologic: no difference in surface, structure, integration, cellular architecture, and subchondral regeneration; contradictory proteoglycan and aggrecan staining. Biochemical: equivalent GAG. Mechanical: tissue derived from MSCs was firmer. MRI: no difference
Ando et al. (2012) [74] 6 piglets Medial femoral condyle chondral defects; cylindrical (8.5 mm diameter) Implantation of isolated, allogeneic synovial MSCs and cultured in a three-dimensional scaffold-free TEC; compared to empty defects 6 months Histologic: tissue containing proteoglycans in the TEC group; empty defects were partially covered with fibrous tissue and showed signs of OA; higher O’Driscoll scores in the TEC group. Mechanical: similar properties between TEC and native cartilage
Zhang et al. (2012) [75] 20 mini-pigs Femoral trochlea chondral defects; cylindrical (6 mm diameter) Implantation of BMDCs or isolated, expanded BM-derived MSCs in type II collagen (porcine) hydrogel; compared to cell-free gels 2 months Macroscopic: good defect filling with both MSCs and BMDCs; irregularity with cell-free gels. Histologic: hyaline-like cartilage with both MSCs and BMDCs; O’Driscoll score was greater in the MSC group at 4 wk, but equivalent between the BMDC and MSC groups at 8 wk
Bekkers et al. (2013) [76] 8 goats Medial femoral condyle chondral defects; cylindrical (5 mm diameter) Implantation of chondrons and BM-derived MSCs suspended in fibrin glue; compared to MFX 6 months Macroscopic: improved defect filling with MSC + chondrons in comparison to MFX. Histologic: O’Driscoll score was significantly higher in the MSC + chondron group. Biochemical: GAG content and GAG/DNA in the repair tissue was greater in the MSC + chondron group than the MFX group
Kamei et al. (2013) [77] 16 mini-pigs Patella chondral defects; cylindrical (6 mm diameter) Magnetic accumulation of injected ferumoxide labeled MSCs; compared to gravity-focused MSCs 3 months Arthroscopic: improved smoothness and integration with magnetic accumulation. Histologic: superior integration and type II collagen content with magnetic accumulation; improved scoring on the Wakitani scale
Nam et al. (2013) [78] 18 goats Medial femoral condyle chondral defects; cylindrical (5 mm diameter) Injection of isolated BM-derived MSCs weekly (×3 wk) starting 2 wk after subchondral drilling; compared to drilling alone 6 months Macroscopic: smooth, integrated tissue with MSCs versus partial, irregular filling with drilling alone. Histologic: O’Driscoll score was significantly higher in the MSC group; improved proteoglycan and type II collagen content with MSCs. Biochemical: higher GAG quantity with MSCs
  1. BM, bone marrow; BMDC, bone marrow-derived cell; GAG, glycosaminoglycan; HA, hyaluronic acid; ICRS, International Cartilage Repair Society; MACI, matrix-associated autologous chondrocyte implantation; MFX, microfracture; MOCART, Magnetic Resonance Observation of Cartilage Repair Tissue; MRI, magnetic resonance imaging; MSC, mesenchymal stem cell; OA, osteoarthritis; PGA, polyglycolic acid; PLA, polylactic acid; PLGA, polylactide co-glycolide; TCP, tricalcium phosphate; TEC, tissue-engineered construct; wk, week(s).