Review Article

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 modelMSCs sourceOther biological adjuvantScaffold materialExperimental time (weeks)Spinal fusion
level
Experimental designMain outcomeReference

Ovariectomized rathPSCs from adipose tissue of patients with and without osteoporosisNELL-1DBM/-TCP
4 weeksL4-L5Group 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
[22]

RatIn toto rat bone marrow from femur flush
(1.1 × 107 cells/mL)
bFGFPEGDA-co-A6ACA hydrogels (poly(ethylene glycol)-diacrylate hydrogel (PEGDA) and N-acryloyl 6-aminocaproic acid (A6ACA))2, 4, 6, and 8 weeksL4-L5Group 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
[23]

RatFresh bone marrow (BM) cells (range, 0.60 to 2.60 × 106 BM cells)rhBMP-2
(0.006 mg/mL)
Absorbable collagen sponge (ACS)8 weeksL4-L5Group 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
[24]

RatExpanded MSCs (3 × 106) from goat BM iliac crest lentivirally transduced to express luciferaseNoneHA/-TCP7 weeksL1-L2 and L4-L5Group 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
[25]

RatExpanded bone marrow from rat femur (1 × 107 cell/mL)NoneSilk fibroin (SF) and mineralized silk fibroin (mSF)12 weeksL4-L5Group 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[26]

RatAllogenic MSCsNone8 weeksL4-L5Group 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
[27]

MouseBone marrow from femur and tibia (1.0 × 108 cells/mL)PRP from donor (1.0 × 109 platelets/mL)
or
rhBMP-2 (31 µg/mL)
ACS4 weeksL4-L5 and L5-L6Group 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
[28]

RatExpanded rat bone marrow from femurs (1 × 106 cells/mL)Fibrin matrixPCL-TCP6 weeksL4-L5Group 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
[29]

RatHuman bone
marrow (5 × 106 MSCs)
NoneTitanium microplates with HA8 weeksL1–L3Group 1: titanium microplates with HA
Group 2: titanium microplates with HA/MSCs
Histology, histomorphometry, and µ-CT revealed no significant bone formation in group 2 in comparison with group 1[30]

RatADSCs (5 × 106 cells/scaffold)
rhBMP-2
or adenoviral vector containing BMP-2 gene
Type-I collagen sponge4 weeksL4-L5Group 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
[31]

RathPSCs from adipose tissueNoneDBM4 weeksL4-L5Group 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
[32]

RatADSCs from healthy donors (1.0 × 106)
Purchased BMSCs (1.0 × 106)
Adenoviral vectors adeno-BMP-2 and adeno-LacZ used to transduce ADSCs and BMSCsACS8 weeksL4-L5Group 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
[33]

RatExpanded BM cells from femurs and tibias
(1 × 106/60 μL)
FGF-4
(41 μg)
HA8 weeksL4-L5Group 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
[34]