TABLE 1.
Summary of the Clinical studies using mesenchymal stromal cells for bone regeneration.
| References | Cell type | Procedure | Patient’s group | Follow-up (average) | Main results |
| Umemura et al., 2006 | Autologous BM-MNCs | Implantation of 1.1 × 109 BM-MNCs in the gastrocnemius muscle around the fractured bone | Tibial non-union with compartment syndrome (N = 1) | 6 months | After treatment: • Marked formation of collateral vessels and slight increase of the callus at the fracture site (4 PO weeks) • Complete fracture healing (6 PO months) |
| Liebergall et al., 2013 | Autologous Purified CD105+ BM cells | Percutaneous injection of 1 × 108 purified CD105+ BM cells mixed with PRP and DBM into the fracture site | Extra-articular distal tibial fracture [Study group (N = 12); Ctrl group (N = 12)] | 12 months | Implantation of CD105+ BM cells into the fracture site significantly reduce time to union |
| Hernigou et al., 2015 | Autologous BMAC | Percutaneous injection of 27.3 ± 14.6 × 106 cells/mL (mean) BMAC | Anckle non-union in diabetic patients [Study group (N = 86); Ctrl group (N = 86)] | 6 months | Treatment with BMAC promoted non-union healing in 82.1% with a low number of complications. • Treatment with iliac bone graft promoted non-union healing in 62.3%, major complications were observed: 5 amputations, 11 osteonecroses of the fracture wound edge and 17 infections. |
| Hernigou and Beaujean, 2002 | Autologous BMAC | Core decompression and injection of 16.4 × 106/mL BMAC | ONFH (N = 116; 189 hips) | 7 years | After treatment: • Hip replacement: 18% (34/189) (Mean: 26 months) • Stage I and II (before collapse) patients: hip replacement 6% (9/145) • Stage III and IV (after collapse) patients: hip replacement 57% (25/44) • Better outcome for a greater number of transplanted progenitor cells |
| Hernigou et al., 2009 | Autologous BMAC | Core decompression and injection of 29 × 106/mL BMAC | ONFH stage I and II (N = 342; 534 hips) | 13 years | After treatment: • Hip replacement: 17.6% 94/534 • Stage I (before collapse): resolution of the ONFH (69/534) • Stage I and II (before collapse) patients: ONFH improvement: (371/534) |
| Cai et al., 2014 | Autologous BM-MNCs and allogeneic UC-MSCs | Arterial perfusion of 60,7 (±11.5) × 106/kg BM-MNCs and 1.0 (±0.1) × 106/kg umbilical cord mesenchymal stromal cells (UC-MSCs) | ONFH (N = 30; 49 hips) | 16.9 months | After treatment: • Relief of hip pain (93.3%), joint function improvement (86.7%), and extended walking distances (86.7%) • Harris hip scores significantly increased (3, 6, and 12- PO months). • MI: bone lesions improvement (89.7%) (44/49) |
| Cella et al., 2011 | Autologous BM-MNCs | Implantation of 426 × 106 BM-MNCs and PRP in a fibrin sponge after BRONJ surgical debridement | Stage III BRONJ (N = 1) | 30 months | After treatment: • Symptoms resolution and progressive mucosal healing (2 PO weeks) • MI: bone regeneration (15 PO months) • Uneventful follow-up • No recurrence of MRONJ |
| Pavan Kumar et al., 2016 | Autologous BM-MNCs | Local transplantation of 2.56 × 108 BM-MNCs [Iliac bone (N = 20)] or 1.74 × 107 BM-MNC [mandible (N = 10)] | Hard tissue defect (N = 15): cystic lesions N = 6 post-surgical alveolar defects N = 4 peri implant defects N = 3 alveolar clefts N = 2 Soft tissue lesion (N = 15): leukoplakia and lichen planus N = 6 OSMF N = 7 post traumatic soft tissue loss N = 2 | 6 months | Hard tissue defect: • MI: bone regeneration, bridging the defect (3 PO months) • MI: Regenerated bone similar to native bone (6 PO months) Soft tissue lesion: • OSMF (7): adequate clinical mouth opening, reduction in burning sensation and blanching of mucosa • Leukoplakia and lichen planus (6): good clinical improvement. • Post traumatic soft tissue defects (2): good clinical improvement. |
| Quarto et al., 2001 | Autologous expanded BM-MSCs | Local application of BM-MSCs on a macroporous HA scaffold in association with external fixation for mechanical stability | Large bone defect (4→7 cm) (N = 3) | 15→27 months | After treatment: • Limb function recovered • Mi: abundant callus formation along the implants, good integration at the interfaces with the host bones (2 PO months) • Uneventful follow-up |
| Marcacci et al., 2007 | Autologous expanded BM-MSCs | Local application of BM-MSCs on a macroporous HA scaffold in association with external fixation for mechanical stability | Large bone defect (4→7 cm) (N = 4) | 1.25→7 years | After treatment: • Complete fusion between the implant and the host bone (5→7 PO months) • Good implant integration (up to 7 PO years) • Uneventful follow-up |
| Morishita et al., 2006 | Autologous cultured BM osteoprogenitors | Implantation of autologous cultured BM osteoprogenitors on HA ceramics in the bone defects after tumor curettage | Benign bone tumors (N = 3): Aneurysmal bone cyst (N = 1) Giant cell tumor (N = 1) Fibrous dysplasia (n = 1) | 29→43 months | After treatment: • MI: Incorporation of the cultured cells into the host bone (3 PO months). • Uneventful follow-up |
| Kitoh et al., 2009 | Autologous expanded BM-MSCs | Injection of 1.23 ± 0.62 107 (femur) or 1.45 ± 0.56 107 (tibia) BM-MSCs and PRP in the site of distraction | Femoral and tibial lengthening [study group (N = 28, 51 bones (23 femora and 28 tibiae)) Ctrl group (60 bones without therapy)] | >3 months | The healing index was significantly lower in the study group • Femoral lengthening showed significantly faster healing than tibial lengthening |
| Kim et al., 2009 | Autologous cultured osteoblasts | Injection of 1.2 107/0.4 ml mixed with fibrin (ratio 1/1) in the fracture area | Long-bone fractures (N = 64) [Study group (N = 32) Ctrl group (N = 32)] | 1→2 months | Autologous cultured osteoblast injection significantly accelerates fracture healing • No complications observed |
| Zhao et al., 2012 | Autologous expanded BM-MSCs | Core decompression and implantation of 2.6 × 106 BM-MSCs in the femoral head | ONFH early stage (N = 100) [Study group (N = 50, 53 hips); Ctrl group (N = 50, 51 hips)] | 5 years | Treatment with core decompression and BM-MSCs, significant improvement the Harris hip score and decreased necrotic bone volume; ONFH progression: 2/53, Subsequent vascularized bone grafting (2/2) • Treatment core decompression: ONFH progression: 10/44, subsequent vascularized bone grafting (5/10) or hip replacement (5/10) |
| Gómez-Barrena et al., 2019 | Autologous BM-MSCs | Application of 100–200 × 106 BM-MSCs mixed with BCP surgically delivered in the non-union site | Fracture non-union (N = 28) | 1 year | Display feasibility and safety of BCP and BM-MSCs in non-union fractures • MI: non-union healing in 26/28 patients (12 PO months) • AP: bone formation surrounding the BCP granules |
| Lendeckel et al., 2004 | Autologous SVF | Application of 295 × 106 SVF mixed with autologous fibrin glue in addition to bone grafting | Calvarial defect (N = 1) | 3 months | After treatment: • MI: new bone formation and near complete calvarial continuity (3 PO months) • Uneventful follow-up |
| Mesimäki et al., 2009 | Autologous expanded AT-MSCs | Application of 13 × 106 AT-MSCs mixed with βTCP and rhBMP-2 in the left rectus muscle. Rectus abdominis free flap (containing the AT-MSCs) raised to reconstruct the bone defect (±10 months later) | Keratocyst (N = 1) | 1 year | After treatment: • MI: bone formation • Dental implants placed in the grafted site • Uneventful follow-up • No recurrence of the keratocyst. |
| Thesleff et al., 2011 | Autologous expanded AT-MSCs | Application of 15 × 106 AT-MSCs mixed with βTCP in the bone defect in association with a mesh to reconstruct the bone defect | Calvarial defect (N = 4) | 3 months (N = 2) 1 year (N = 2) | After treatment: • good clinical outcome • Medical imaging: bone regeneration • No complication observed. |
| Sándor et al., 2013 | Autologous expanded AT-MSCs | Application of 106 AT-MSCs mixed with βTCP and rhBMP-2 in association with a mesh to reconstruct the bone defect | Ameloblastoma (N = 1) | 3 years | After treatment: • MI: bone formation • No complication observed • Dental implants placed in the grafted site. • No recurrence of the ameloblastoma |
| Sándor et al., 2014 | Autologous expanded AT-MSCs | Application of 2.8→16 × 106 AT-MSCs mixed with βTCP (N = 10) or BAG (N = 3) to reconstruct the bone defect | Cranio-maxillofacial defects (=13): Frontal sinus (N = 3) Cranial bone (N = 5) Mandible (N = 3) Nasal septum (N = 2) | 37 months | After treatment: • Successful integration of the construct to the surrounding skeleton (10/13) • Two cases of cranial defect needed a second procedure • One case of septal perforation failed |
| Khalpey et al., 2015 | Autologous uncultured SVF | Local injection: 100 × 106 SVF and intravenous injection: 200 × 106 SVF in association with conventional plating system | Sternal non-union with bone defect (N = 1) | months | After treatment: • Stabilized sternum with nearly no pain and normal exercise tolerance • MI: fracture healing and closure of areas of non-union (3, 6 PO months) • Uneventful follow-up |
| Saxer et al., 2016 | Autologous uncultured SVF | Application of SVF mixed with Ceramic granules and fibrin hydrogel in the void space of the fracture zone upon ORIF | Displaced low-energy fractures of the proximal humerus (N = 8) | 12 months | SVF, without expansion or exogenous priming, can spontaneously form bone tissue and vessel structures within a fracture-microenvironment After treatment: • Pain-free range of movement sufficient (within a year) • AP: de novo bone formation (5/6) • Uneventful follow-up |
| Prins et al., 2016 | Autologous uncultured SVF | Local application of SVF mixed with BCP (N = 5) or βTCP (n = 5) | MSFE (N = 10) | >2.5 years | Display feasibility, safety, and efficiency of SVF seeded on bone substitutes for MSFE. • AP: Bone and osteoid percentages were higher in the SVF group, independent of the bone substitute • No adverse effects |
| Farré-Guash et al., 2018 | Autologous uncultured SVF | Local application of SVF mixed with BCP (N = 5) or βTCP (n = 5) | MSFE (N = 10) | Display feasibility, safety, and efficiency of SVF seeded on bone substitutes for MSFE • Pro-angiogenic effect of SVF • AP: correlation between bone percentages and blood vessel formation, bone percentage higher in the SVF group in the cranial area. • No adverse effects |
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| Bouland et al., 2020 | Autologous uncultured SVF | Local application of, 48.1 × 106 SVF injected in L-PRF after bone debridement (Case 1) Local application 20.8 × 106 SVF injected in L- PRF after bone debridement (Case 2) | MRONJ (N = 2) | 2 years | Case 1: After treatment: • Symptoms resolution and mucosal closure (2 PO weeks) • MI: bone formation (6, 12, 18 PO months) • Uneventful follow-up • No recurrence of MRONJ Case 2: After treatment: • Symptoms resolution and mucosal closure (2 PO weeks) • MI: bone formation (6,12,18 PO months) • Uneventful follow-up • No recurrence of MRONJ |
| Dilogo et al., 2017 | Allogeneic expanded UC-MSCs | Application of 50 × 106 UC-MSCs mixed with HA and BMP-2 and mechanical stimulation (Masquelet technique) | Infected non-union Femoral fracture with a bone defect (N = 1) | 12 months | After treatment: • Clinical union, walking with a crutch, no pain during the walk and clinical leg length discrepancy (2 cm). LEFS improvement at 30% (6 PO months) • Full weight bearing walk without pain, with an improved LEFS and no leg length discrepancy (11 PO months) • MI: progressive bone formation (1, 3, 6, 9, 12 PO months) • Uneventful follow-up |
| Rahyussalim et al., 2020 | Allogeneic expanded UC-MSCs | Application of 20 × 106 UC-MSCs mixed with HA after surgical debridement to reconstruct the bone defect | Vertebral body bone defect (N = 1) | 6 months | After treatment: • Walking without pain (3 PO months). • Uneventful follow-up • No signs of neoplasm formation, no significant bone deformation or spinal cord compression. |
| Manimaran et al., 2014 | Autologous expanded DP-MSCs and uncultured BMAC | Application of BMAC mixed with βTCP and HA after curettage of the necrotic bone (Case 1) Application of DPMSC mixed with βTCP and PRP after curettage of the necrotic bone (Case 2) | ORN (N = 2) | Case 1: 2 years Case 2: 6 months | Case 1: After treatment: • gradual pain reduction and no intraoral discharge (2 PO months) • MI: bone formation (2 PO months) and resolution of the suspected fracture line (6 PO months) • Follow-up uneventful • No recurrence of the ORN Case 2: After treatment: • MI: bone formation (2, 6 PO months) • Follow-up uneventful • No recurrence of the ORN |
| Manimaran et al., 2016 | Autologous expanded DP-MSCs and uncultured SVF | Application of 20 × 106 DPMSC and 45 × 106 SVF mixed with PRP and βTCP, covered with PRF in association with a mesh to reconstruct the bone defect after resection of the ameloblastoma | Ameloblastoma (N = 1) | 1.5 years | After treatment: • MI: bone formation (10 PO months) • Follow-up uneventful • No recurrence of the ameloblastoma |
βTCP, β-tricalcium phosphate; AP, anatomopathology; BAG, bioactive glass; BCP, biphasic calcium phosphate; BMAC, bone marrow aspirate concentrate; BM-MSC, bone marrow mesenchymal stromal cell; BM-MNC, bone marrow mononuclear cell; BRONJ, bisphosphonate-related osteonecrosis of the jaw; CT, computed tomography; DBM, demineralized bone matrix; HA, hydroxyapatite; LEFS, lower extremity function scale; MI, medical imaging; MSFE, maxillary sinus floor elevation; MRONJ, medication-related osteonecrosis of the jaw; ONFH, osteonecrosis of the femoral head; ORIF, open reduction internal fixation; ORN, osteoradionecrosis; OSMF, oral sub-mucous fibrosis; rhBMP-2: PRP, platelet-rich plasma; L-PRF, leukocyte-platelet rich fibrin.