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