Table 1.
Chondrogenic in vivo preclinical experimental mesenchymal stem cell studies in sheep.
| Model type | Number of animals | Model defect size/study period | Biomaterial used | Cell dose | Evaluation criteria | Overall result | References |
|---|---|---|---|---|---|---|---|
| Medial femoral condyle defect | 28 (n = 16 cell along β-TCP with treated; n = 8 in β-TCP only and n = 4 in control) | 8 mm (diameter) and 4 mm (depth)/24 weeks | Autologous BM-MSCs + beta-tricalcium phosphate (β-TCP) | 3 × 107 | Macroscopic observation, histological, immuno-histochemical, biochemical analysis | Experimental animal defects were resurfaced with hyaline-like tissue. An ideal interface formed between the engineered cartilage, adjacent normal cartilage, and the underlying bone | Guo et al. (2004) |
| Osteonecrosis of femoral head | 8 animals (4 in control group; 2 each in sheep MSC group and human MSC group treated after 8 weeks of induced necrosis) | 10 mL of absolute ethanol induced | Sheep BM-MSCs (transfected) and human dental stem cells | 1 × 106 (each cell type) | Light microscopy | Better bone regeneration in cell treated group animals | Feitosa et al. (2010) |
| Chronic model of medial femoral condyles osteochondral lesions | 10 (40 defects; group I: chondrogenically differentiated MSC/hydrogel constructs; group II: undifferentiated ovine MSC/hydrogel constructs; Group III: cell free hydrogel; group IV: control | 7 mm/ 6 months | Autologous BM-MSCs/collagen I hydrogel constructs | 4 ×105 MSCs mixed with collagen I | Histopathology | Group I had significantly better histologic scores with morphologic characteristics of hyaline cartilage such as columnarization and presence of collagen type II compared to others. However, each group showed variability in results | Zscharnack et al. (2010) |
| Chronic model of anterior cruciate ligament excision | 16; 6 animals in group I (pre-differentiated MSCs and II (undifferentiated MSCs) and 4 (control group) | 6 weeks | Chondrogenically differentiated MSCs or undifferentiated MSCs | 10 × 106 per joint | Gross, histological and clinical observation | Retardation of osteoarthritis in cell treated groups. Non-significant difference in group I and II except for macroscopic observations of meniscus repair. Severe osteoarthritis in control | Al Faqeh et al. (2012) |
| Chronic model full thickness medial femorotibial condyles and meniscal tear | 10 (20 defects 10 studied at 6 months period while other 10 at 12 months period) one of the limbs remained control | 60 mm defect size/6 months or 12 months | BM-MSCs | 1.1 × 107 (6 month period animals) or 1.2 × 107 (12 month period animals) | Radiography, MRI, ultrasound, macroscopic and histological analyses | Regeneration of articular cartilage and meniscus was case-dependent but statistically significant improvement was found in specific macroscopic and histological parameters | Caminal, Moll, et al. (2014) |
| Medial femoro-tibial condyle defect | 9 (18 defects) | 7 mm defect size/4 and 12 months | BM-MSCs alone or seeded on co-polymeric poly-lactide:polyglycolic acid scaffolds either | 3.3 × 106±0.4 × 106 cells | Biomechanical testing, macroscopic and histological analyses | Better macroscopic scores at 4 months in cell treated compared to 12 months evaluation period. Non-significant histopathological scores at 12 months between cell treated and cell free groups | Caminal, Fonseca, et al. (2014) |
| Chronic anterior cruciate ligament transection and medial meniscectomy | 18 (6 animals in each group) Group I: BM-MSCs; group II: bone marrow mononuclear cells; group III: control | 8 weeks | Autologous BM-MSCs | 10 × 106 after 12 weeks of model creation | Macroscopically and histologically, and glycosaminoglycan (GAG) contents, gene expression levels (collagen II, aggrecan and matrix metalloproteinase-13), tumor necrosis factor-α (TNF-α) and transforming growth factor beta | Significantly higher cartilage regeneration and lower proteoglycan loss in group I than group II. Comparable inhibition of PGE2, TNF-α and TGF-β levels in synovial fluid and promotion of higher levels of Aggrecan and Col II in two cell treated groups. Down regulation of MMP-13 also comparable. Both the cell treated groups had significantly better cartilage than control | Song et al. (2014) |
| Full thickness lateral femoral condyle defect | Group I (amniotic membrane); group II (cryopreserved amniotic membrane previously cultivated 12 (4 each group) with BM-MSCs; group III (cryopreserved amniotic membrane alone); group IV (control) | 7 × 5 mm/8 weeks | BM-MSCs and amniotic membrane | 2 × 106 cells and amniotic membrane | Gross and histopathology | Significant difference between treatment and control group. Non-significant differences in treatment groups | Garcia et al. (2014) |
| Partial thickness medial femoral condyle defect | 15 animals/ 30 knees (group I: scaffold plus cell; group II; scaffold only; group III control) | 10 mm/6 months | Xenogenic AD-MSCs and collagen/chitosan scaffold | 1 × 106 along with scaffold | Microscopic and macroscopic analysis | Significantly higher histological scores in cell treated group compared to others | Zorzi et al. (2015) |
| Unilateral medial meniscectomy | 20 (Group I: 6 animals, BM-MSCs + scaffold; Group II: 6 animals BM concentrate + scaffold; group III: 4 animals scaffold treated group IV: 4 animals, control | 12 weeks | BM-MSCs + scaffold (Hyaff®-11) and BM concentrate + scaffold (Hyaff®-11) | 6 × 106 seeded on scaffold | Macroscopy, histology, immunohistochemistry, and micro-computed tomography | BM concentrate better inhibited inflammation in cartilage, meniscus, and synovium. It also improved cartilage healing. subchondral bone thickness decreased in both the cell treated groups | Desando et al. (2016) |
| Meniscal cartilage tear model | 30 animals (3 groups with 10 animals in each group evaluated at 13 weeks and 6 months). Group I: scaffold laden MSCs; group II: scaffold only and group III: suturing only) | 5 × 3 mm/13 weeks and 6 months | BM-MSCs collagen I scaffold | 1 × 106/cm2 | Macroscopy and histopathology | Statistically significant improvement in cell treated compared to control at 13 weeks. But no difference at 6 months period | Whitehouse et al. (2017) |
| Anterior cruciate ligament resection and medial meniscectomy | Group I: AD-MSCs and hyaluronic acid; group II: hyaluronic acid and group III: control) | 14 weeks after treatment | Allogenic AD-MSCs and Hyaluronic acid | 5 × 107 cells at 3 weeks) and low (1 × 107 cells at 6 weeks) | Magnetic resonance imaging (MRI), macroscopy, micro-computed tomography, and cartilage-specific staining | AD-MSCs + hyaluronic acid could efficiently block osteoarthritis progression and promote cartilage regeneration. | Feng et al. (2018) |