Table 1.
Preclinical studies using MSCs and biomaterials for the treatment of bone segmental defects.
| References | Cells | Biomaterials | Animal Model | Outcome |
|---|---|---|---|---|
| Bruder et al. (1998) | Canine BMSCs (7.5 × 106/ml) | Three groups used: 1) HA-TCP-BMSCs, 2) HA-TCP, 3) Untreated |
Segmental femoral bone defect (2.1 cm) in canine model | - At 16 weeks, radiographic union was established rapidly at the interface between the host bone and the HA-TCP-BMSCs implants only - Both woven and lamellar bone had filled the pores of the HA-TCP-BMSCs implants |
| Kon et al. (2000) | Ovine BMSCs (2.5 × 105/ml) | Two groups used: 1)HA-BMSCs 2) HA |
Segmental tibial bone defect (3.5 cm) in ovine model | -At 2 months, extensive bone formation in HA-BMSCs implants within the macropore space and around the implant - Stiffness higher in HA-BMSCs implant/bone complex compared to HA control group |
| Arinzeh et al. (2003) | Canine BMSCs (7.5 × 106/ml) | Three groups used: 1) HA-TCP-allogeneic BMSCs 2) HA-TCP 3) Untreated |
Segmental femoral bone defect (2.1 cm) in canine model | - No lymphocytic infiltration occurred and no antibodies against allogeneic cells were detected - At 16 weeks, new bone had formed throughout the HA-TCP-allogeneic BMSCs implant |
| Bensaïd et al. (2005) | Ovine BMSCs (1 × 107/ml) | Four groups used: 1)Coral HA-BMSCs 2) Coral HA 3) Autologous bone graft 4) Untreated |
Segmental metatarsus bone defect (2.5 cm) in ovine model | - At 4 months, coral HA-BMSCs implants show the same amount of newly formed bone - with autologous bone and at 14 months are completely replaced by newly formed, structurally competent bone |
| Viateau et al. (2007) | Ovine BMSCs (8.28 ± 1.32 × 106/implant) | Three groups used: 1) Coral-BMSCs 2) Coral 3) Untreated |
Segmental metatarsus bone defect (2.5 cm) in ovine model | -At 6 months, radiographic, histological, and computed tomographic tests performed showed that the osteogenic abilities of the coral-BMSCs implants were significantly greater than those of coral scaffold alone |
| Zhu et al. (2006) | Caprine BMSCs (20 × 106/ml) | Two groups used: 1) Coral-BMSCs 2) Coral |
Segmental femoral bone defect (2.5 cm) in caprine model | -At 4 months bony union was observed in coral-BMSCs implant and engineered bone was further remodeled into newly formed cortexed bone at 8 months |
| Mastrogiacomo et al. (2007) | Ovine BMSCs (0.5–1.0 × 108/ml) | Two groups used: 1) Si-TCP-BMSCs 2) Si-TCP |
Segmental tibial bone defect (4 cm) in ovine model | - At 4 months, 4 out of 5 animals implanted with Si-TCP-BMSCs implants, a progressive new bone formation, from the osteotomy defect edge toward the implant mid zone, was observed - Neither bone formation nor scaffold resorption was observed in Si-TCP group |
| Liu et al. (2008) | Caprine BMSCs (2 × 107/ml) | Three groups used: 1) β-TCP-BMSCs 2) β-TCP 3) Untreated |
Segmental tibial bone defect (2.6 cm) in caprine model | -At 32 weeks, bony union can be observed at β-TCP-BMSCs group by gross view, X-ray and micro-computed tomography detection, and histological observation - In β-TCP-BMSCs group the implants are almost completely replaced by tissue-engineered bone whereas bone mineral density is significantly higher than in β-TCP group |
| Giannoni et al. (2008) | Ovine BMSCs (70–100 × 106) | Three groups used: 1) HA-Si-TCP-BMSCs 2) HA-Si-TCP 3) Autologous bone graft |
Segmental tibial bone defect (4.5 cm) in ovine model | -At 20–24 weeks, autologous bone graft group performed best -as assessed radiologically - In other groups very limited healing was detected whereas a partial bone deposition occurred at the periphery of the bony stumps only in HA-Si-TCP-BMSCs group |
| Nair et al. (2008) | Caprine BMSCs (1 × 105/cm2) | Two groups used: 1)HASi + BMSCs 2) HASi |
Segmental femoral bone defect (2 cm) in caprine model | -At 4 months, both HASi + BMSCs and HASi implants showed good osteointegration and osteoconduction - The superior performance of HASi + BMSCs implant was evident by the lamellar bone organization of newly formed bone throughout the defect together with the degradation of the material |
| Niemeyer et al. (2010) | Human and Ovine BMSCs (2 × 107/ml) | Three groups used: 1)HA-COL-human BMSCs 2) HA-COL-ovine BMSCs (allogeneic) 3) Untreated |
Segmental tibial bone defect (3 cm) in ovine model | - At 26 weeks, radiology and histology demonstrated significantly better bone formation in HA-COL-ovine BMSCs group compared to HA-COL-human BMSCs and untreated groups |
| Nair et al. (2009) | Caprine BMSCs (1 × 105 cm2) | Three groups used: 1)HASi + BMSCs 2) HASi + BMSCs + PRP 3) HASi |
Segmental femoral bone defect (2 cm) in caprine model | -At 2 months, in HASi + BMSCs and HASi + BMSCs + PRP groups 60–70% of the mid region of the defect was occupied by woven bone, in line with material degradation |
| Zhu et al. (2010) | Caprine BMSCs (5 × 107/ml) | Two groups used: 1)Coral-BMSCs 2) Coral-AdBMP-7- BMSCs |
Segmental femoral bone defect (2.5 cm) in caprine model | -Much callus was found in the coral-AdBMP-7- BMSCs group, and nails were taken off after 3 months of implantation, indicating that regenerated bone in the defect can be remodeled by load-bearing, whereas this happened after 6 months in the coral-BMSCs group |
| Cai et al. (2011) | Canine BMSCs (20 × 106/ml) | Four groups used: 1) Coral HA-BMSCs 2) Coral HA-BMSCs (vascularized) 3) Coral HA (vascularized) 4) Coral HA |
Segmental fibula bone defect (1 cm) in canine model | - At 3 months, vascularization improved 2-fold bone formation compared to non-vascular group |
| Reichert et al. (2012) | Ovine BMSCs (35 × 106 cells/250 μl) BMP-7 (3.5 mg/implant) | Five groups used: 1)mPCL-TCP-BMSCs + PRP 2) mPCL-TCP-BMP-7 3) mPCL-TCP 4) Autologous bone graft 5) Untreated |
Segmental tibial bone defect (3 cm) in ovine model | - At 12 months, biomechanical analysis and microcomputed tomography imaging showed significantly greater bone formation and superior strength for the biomaterial loaded with rhBMP-7 compared to the autograft |
| Manassero et al. (2013) | Ovine BMSCs (7.5 ± 1.2 × 106/implant) | Two groups used: 1) Coral-BMSCs 2) Coral |
Segmental metatarsus bone defect (2.5 cm) in ovine model | -At 6 months, coral-BMSCs implants showed 2-fold increase in bone formation compared to coral alone |
| Berner et al. (2013) | Ovine BMSCs (35 × 106/500 μl) | Four groups used: 1)mPCL-TCP-BMSCs (autologous) 2) mPCL-TCP-BMSCs (allogeneic) 3) mPCL-TCP 4) Autologous bone graft |
Segmental tibial bone defect (3 cm) in ovine model | -At 12 weeks radiology, biomechanical testing and histology revealed no significant differences in bone formation between the autologous and allogenic mPCL-TCP-BMSCs groups - Both cell groups showed more bone formation than the biomaterial alone |
| Fan et al. (2014) | Non-human primate BMSCs (5 × 106/implant) | Five groups used: 1) TCP-β-BMSCs 2) TCP-β-BMSCs-fascia flap 3) TCP-β-BMSCs-saphenous vascular bundle 4) TCP-β 5) Untreated |
Segmental tibial bone defect (2 cm) in non-human primate model | -At 4, 8, and 12 weeks, the TCP-β-BMSCs-saphenous vascular bundle group could augment new bone formation and capillary vessel in-growth. It had significantly higher values of vascularization and radiographic grading score compared with other groups. |
| Yoon et al. (2015) | Canine ADMSCs (1 × 106/50 μl) | Five groups used: 1) ASA-ADMSCs 2) ASA-β-TCP-ADMSCs 3) ASA-β-TCP 4) ASA 5) Untreated |
Segmental ulna bone defect (1.5 cm) in canine model | - At 16 weeks, histomorphometric analysis showed that ASA biomaterials with ADMSCs had significantly greater new bone formation than other groups |
| Berner et al. (2015) | Ovine BMSCs (100 × 106) | Three groups used: 1) PCL-HA-allogeneic BMSCs 2) PCL-HA 3) Autologous bone graft |
Segmental tibial bone defect (3 cm) in ovine model | - Minimally invasive percutaneous injection of allogeneic BMSCs into biodegradable composite biomaterials 4 weeks after the defect surgery led to significantly improved bone regeneration compared with preseeded biomaterial/cell and biomaterial-only groups |
| Masaoka et al. (2016) | Non-human primate BMSCs (1.3–4.1 × 106/ml) | Two groups used: 1) β-TCP-BMSCs 2) β-TCP |
Segmental femoral bone defect (5 cm) in non-human primate model | -At 8–15 months, five of the seven animals treated with β-TCP-BMSCs implant showed successful bone regeneration |
| Smith et al. (2017) | Ovine BMSCs (1 × 107/implant) | Three groups used: 1) PLLA-PCL-BMSCs 2) PLLA-PCL 3) Untreated |
Segmental tibial bone defect (3.5 cm) in ovine model | -At 12 weeks, both PLLA-PCL-BMSCs and PLLA-PCL groups showed enhanced quantitative bone regeneration - Significant bone regeneration was evident only in the PLLA-PCL-BMSCs group whereas complete defect bridging was not achieved in any group |
| Berner et al. (2017) | Ovine MPCs, mOB, tOB (35 × 106 cells) | Four groups used: 1)mPCL-TCP-PRP 2) mPCL-TCP-allogenic-MPC 3) mPCL-TCP-allogenic-mOB 4) mPCL-TCP-allogenic-tOB |
Segmental tibial bone defect (3 cm) in ovine model | -At 6 months, mPCL-TCP-allogenic-MPC group showed a trend toward a better outcome in biomechanical testing and the mean values of newly formed bone |
BMSCs, bone marrow tissue-derived MSCs; ADMSCs, adipose tissue-derived MSCs; MPCs, mesenchymal progenitor cells; tOBs, axial skeleton osteoblasts; mOBs, orofacial skeleton osteoblasts; PRP, platelet rich plasma; HA, hydroxyapatite; HA-TCP, hydroxyapatite-tricalcium phosphate; HA-COL, hydroxyapatite-collagen; Coral HA, coral hydroxyapatite; HASi, triphasic ceramic-coated hydroxyapatite; Si-TCP, silicon stabilized tricalcium phosphate; mPCL-TCP, medical grade polycaprolactone-tricalcium phosphate; ASA, autologous serum-derived albumin; PCL-HA, polycaprolactone-hydroxyapatite; PLLA-PCL, poly(L-lactic acid)-poly(ε-caprolactone); AdBMP-7, adenovirus mediated bone morphogenetic protein 7.