Mesenchymal Stem Cells for the Treatment of Spinal Arthrodesis: From Preclinical Research to Clinical Scenario
Table 1
Published in vivo studies in small animal models on mesenchymal stem cells for spinal arthrodesis procedures.
Animal model
MSCs source
Other biological adjuvant
Scaffold material
Experimental time (weeks)
Spinal fusion level
Experimental design
Main outcome
Reference
Ovariectomized rat
hPSCs from adipose tissue of patients with and without osteoporosis
NELL-1
DBM/-TCP
4 weeks
L4-L5
Group 1: DBM/β-TCP with hPSCs (0.25 × 106 cells/mL) Group 2: DBM/β-TCP with hPSCs (0.75 × 106 cells/mL) Group 3: DBM/β-TCP with NELL-1 (33.3 μg/mL) Group 4: DBM/β-TCP with NELL-1 (66.6 μg/mL) Group 5: DBM/-TCP with hPSCs/NELL-1 at the dosage of groups 1 and 3 Group 6: DBM/-TCP with a hPSCs/NELL-1 at the dosage of groups 2 and 4
(i) Group 1 achieved a fusion rate of 20% (1/5), group 2 of 28.6% (2/7), groups 3 and 4 of 20% (1/5), and group 5 of 37.5% (3/8), and group 6 improved the fusion rates up to approximately 83.3% (5/6) (ii) Microcomputed tomography imaging and quantification further confirmed solid bony fusion in group 6
Group 1: scaffold with bone marrow Group2: scaffold with bFGF Group 3: scaffold with saline solution
(i) Radiographs showed fusion masses in 4 animals out of 7 in each group at 2 weeks. At 4 weeks, all animals showed clear evidence of hard tissue formation, with progressively increase at 6 and 8 weeks (ii) -CT imaging at 8 weeks revealed a 51% of mineralized hard tissue for group 3, 59% for group 2, and 54% for group 1 (iii) Manual palpation provided evidence of fusion in all groups, with no significant differences in fusion indices
Fresh bone marrow (BM) cells (range, 0.60 to 2.60 × 106 BM cells)
rhBMP-2 (0.006 mg/mL)
Absorbable collagen sponge (ACS)
8 weeks
L4-L5
Group 1: 2ACS with fresh BM and rhBMP-2 Group 2: 2ACS with rhBMP-2 Group 3: 1ACS with rhBMP-2 Group 4: ACS with BM Group 5: ACS alone
(i) In group 1 BM plus rhBMP-2/ACS significantly increased the fusion rate to 89% (16/18) compared with a base fusion rate of 33% (4/12) in group 3 and 50% (6/12) in group 2 () (ii) No difference in strength or stiffness was detected among group 1 and groups 2 and 3. (iii) No fusion or bone formation was observed in the rats of groups 4 and 5
Expanded MSCs (3 × 106) from goat BM iliac crest lentivirally transduced to express luciferase
None
HA/-TCP
7 weeks
L1-L2 and L4-L5
Group 1: no cells Group 2: MSCs Group 3: MSCs gamma-irradiated (30 Gy) Group 4: MSCs dipped in liquid N2
(i) The antiluciferase immunohistochemistry showed no newly formed bone or luciferase-positive cells. (ii) Histological staining with Hematoxylin/Eosin highlighted no signs of a bone formation in any groups
Expanded bone marrow from rat femur (1 × 107 cell/mL)
None
Silk fibroin (SF) and mineralized silk fibroin (mSF)
12 weeks
L4-L5
Group 1: SF scaffold Group 2: SF with MSCs Group 3: mSF Group 4: mSF with MSCs Group 5: autograft Group 6: sham group
Fusion rate, bone volume, biomechanical parameters, and histological score showed no significant differences between group 4 and group 5. Group 3 was significantly greater for most parameters than group 2
Group 1: trinity evolution (DBM with MSCs) Group 2: grafton (DBM) Group 3: DBM Group 4: decortication only
(i) Fusion rate by radiography was 8/8 for group 1, 3/8 for group 2, and 5/8 for group 3 (ii) Fusion rate by -CT and manual palpation was 4/8 for group 1, 3/8 for group 2, and 3/8 for group 3
Bone marrow from femur and tibia (1.0 × 108 cells/mL)
PRP from donor (1.0 × 109 platelets/mL) or rhBMP-2 (31 µg/mL)
ACS
4 weeks
L4-L5 and L5-L6
Group 1: collagen sponge with rhBMP-2 and saline solution Group 2: collagen sponge with rhBMP-2 and PRP Group 3: collagen sponge with rhBMP-2 and BM Group 4: decortication only
(i) Fusion appeared radiographically and histologically similar in all three experimental groups (ii) The area, volume, and density of the fusion mass were significantly greater () for group 3 as compared with group 1 (iii) Group 2 had intermediate fusion area and density (iv) No spinal fusion was detected in group 4
Expanded rat bone marrow from femurs (1 × 106 cells/mL)
Fibrin matrix
PCL-TCP
6 weeks
L4-L5
Group 1: 10 µg of rhBMP-2 with 1 × 106 undifferentiated BMSCs Group 2: 10 µg of rhBMP-2 with osteogenic-differentiated BMSCs Group 3: 2.5 µg rhBMP-2 with undifferentiated BMSCs Group 4: 2.5 µg rhBMP-2 with osteogenic-differentiated BMSCs Group 5: 0.5 µg rhBMP-2 with undifferentiated BMSCs Group 6: 0.5 µg rhBMP-2 with osteogenic differentiated BMSCs
(i) Predifferentiation of BMSCs before transplantation failed to promote posterolateral spinal fusion when codelivered with low-dose of rhBMP-2 in group 5 as 17% fusion rate was observed (1/6) (ii) In contrast, combined delivery of undifferentiated BMSCs with low-dose BMP-2 (2.5 µg) as in group 5 demonstrated significantly higher fusion rate (4/6 or 67%) as well as significantly increased volume of new bone formation
rhBMP-2 or adenoviral vector containing BMP-2 gene
Type-I collagen sponge
4 weeks
L4-L5
Group 1: ADSCs transduced with an adenoviral vector containing rhBMP-2 gene Group 2: ADSCs with osteogenic media and 1 mg/mL of recombinant rhBMP-2 Group 3: rhBMP-2 (10 mg) Group 4: rhBMP-2 (1 mg) Group 5: ADSCs
(i) All animals of group 1 were characterized by fusion masses (8/8) after 4 weeks (ii) Group 1 revealed spinal fusion at the cephalad level (L3 and L4) (iii) New bone formation in groups 1 was significantly larger than those in any other treatment group () (iv) Groups 3 and 4 showed a solid fusion in 8/8 and 4/8 animals, respectively (v) Groups 2 and 5 showed no fusion
Group 1: DBM Group 2: DBM with 0.15 × 106 hPSCs Group 3: DBM with 0.50 × 106 hPSCs Group 4: DBM with 1.50 × 106 hPSCs
(i) hPSC treatment (groups 2, 3, and 4) significantly increased spinal fusion rates in comparison with group 1 (ii) Groups 2, 3, and 4 resulted in fusion rates of 100%, 80%, and 100%, respectively, compared with 20% fusion in group 1 (iii) Computerized biomechanical simulation (finite element analysis) further demonstrated bone fusion in hPSC treatment groups (iv) Histological analyses showed endochondral ossification in hPSC-treated samples
Adenoviral vectors adeno-BMP-2 and adeno-LacZ used to transduce ADSCs and BMSCs
ACS
8 weeks
L4-L5
Group 1 ACS with ADSCs transfected with adeno-BMP-2 Group 2 ACS with BMSCs transfected with adeno-BMP-2 Group 3 ACS with rhBMP-2 Group 4 ACS with ADSCs transfected with adeno-LacZ Group 5 ACS with BMSCs transfected with adeno-LacZ, and Group 6 ACS
(i) Spinal fusion was observed in groups 1, 2, and 3 rats (ii) 75% (15/20) of the animals of groups I and II had spontaneous extension of the fusion to a second level (iii) No animals in groups 4, 5, and 6 rats developed fusion (iv) New bone volume was significantly greater in groups 1 and 2 than in group 4
Expanded BM cells from femurs and tibias (1 × 106/60 μL)
FGF-4 (41 μg)
HA
8 weeks
L4-L5
Group 1: HA Group 2: HA with MSCs Group 3: HA with MSCs and FGF-4
(i) Radiographic, high-resolution -CT, and manual palpation revealed spinal fusion in 5/6 (83%) in group 2 (ii) In group 1, 3/6 (60%) rats developed fusion at L4-L5 by radiography and 2/5 (40%) by manual palpation in radiographic examination (iii) In group 3, bone fusion was observed in only 50% of rats by manual palpation and radiographic examination