Mesenchymal Stem Cells for the Treatment of Spinal Arthrodesis: From Preclinical Research to Clinical Scenario

Table 3

Published in vivo studies in large 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
Pig	ADSCs from inguinal subcutaneous tissue	None	DBM	8 and 12 weeks	L2–L6	Group 1: one cage was left and three filled with freeze dried irradiated cancellous pig bone graft; Group 2: freeze dried irradiated cancellous pig bone graft; Group 3: cancellous bone autograft; Group 4: bone graft with 3D osteogenic differentiated ADSCs	-CT scan, microradiography, and histology/histomorphometry demonstrated a significant increase in bone content in group 4	[50]
Sheep	Expanded and osteogenic induced BMSCs from iliac crest; (5-6 × 10^7)	Fibrin	TCP/HA	12 weeks	L1–L6	Group 1: HA with MSCs; Group 2: TCP/HA with MSCs; Group 3: autograft	(i) Radiography, manual palpation, histological analysis, and SEM analyses revealed demonstrated better bone formation in group 2 compared to group 1; (ii) Histomorphometry detected 55.8% of new bone in group 3, followed by group 2 (42.7%) and group 1 (10.7%)	[51]
Sheep	Allogenic sheep mesenchymal precursor cells (MPCs) from BM from iliac crest	None	HA/TCP	16–36 weeks	L2–L5	Group 1: autograft; Group 2: HA/TCP; Group 3: HA/TCP with MPCs (25 × 10^6); Group 4: HA/TCP with MPCs (75 × 10^6); Group 5: HA/TCP with MPCs (225 × 10^6)	Computed tomography, high-resolution radiography, biomechanical testing, organ pathology, bone histopathology,; and bone histomorphometry showed that allogeneic mesenchymal precursor cells produced fusion efficacy similar to that achieved using iliac crest autograft	[52]
Sheep	Allogenic MPCs from BM from sheep iliac crest	None	HA/TCP	16 weeks	L4-L5	Group 1: autograft; Group 2: HA/TCP with MPCs (2.5 × 10^6); Group 3: HA/TCP with MPCs (6.5 × 10^6); Group 4: HA/TCP with MPCs (12.5 × 10^6)	(i) Manual palpation of the fusion site indicated solid fusion in more than 75% of MPC-treated group and 65% of group 1; (ii) Computed tomography and histomorphometry analyses showed all animals in the MPCs groups and group 1 fusion masses were present at 16 weeks	[53]
Sheep	Expanded and osteoinduced BM from iliac crest	None	HA	6 months	L4-L5	Group 1: autograft; Group 2: allograft; Group 3: HA; Group 4: HA with MSCs.	(i) By CT scan and histology lumbar fusion were higher for groups 1 and 2 (70%) than for group 3 (22%) and group 4 (35%); (ii) New bone formation was higher for groups 1 and 2; (iii) Group 4 had a better fusion rate than group 3, but the histology showed no significant differences between them in terms of quantity of bone formation	[54]
Sheep	BM concentrate (1.5 × 10^6 in 0.2 mL)	None	Natural bone collagen scaffold (NBCS) from human organic bone particles	6 and 10 weeks	L3-L4 and L4-L5	Group 1: autograft; Group 2: NBCS; Group 3: BMCs; Group 4: NBCS with BMCs	(i) Solid spinal fusion was achieved in all six segments (6/6) in group 4 at 10 weeks, compared with 4/8 segments in group 1, 2/8 segments in group 2, and 3/6 segments in group 3; (ii) The biomechanical stiffness of fusion masses and bone volume at the fusion site were higher in group 4 (p < 0.05); (iii) At 10 weeks, the radiographic score reached was significantly higher in group 4 than in groups 1, 2 and 3; (iv) Histological findings revealed that group 4 induced new bone formation integrated well with host bone tissue	[55]
Ewes	Allogenic MPCs (5 × 10^6); or; allogenic amnion epithelial stem cells; (5 × 10^6 AECs)	None	Fidji interbody cage made from polyetheretherketone; and HA/TCP	3 months	C3-C4	Group 1: cage packed with autograft; Group 2: cage packed with HA/TCP; Group 3: cage packed with HA/TCP and MPCs; Group 4: cage packed with HA/TCP and AECs; Group 5: controls	(i) Significant fusion mass was detected in group 3 compared to that in groups 1, 2, or 4; (ii) CT scan at 3 months revealed that 5/6 animals in group 3 (83%) had continuous bony bridging compared with 0/ 5 of group 4 and 1/6 of group 1 and 2/6 of group 2 (p < 0.01)	[56]
Ewes	Allogeneic MPCs; (5 × 10^6 or 10 × 10^6)	None	Fidji interbody cage made from polyetheretherketone; and HA/TCP	3 months	C3-C4 anterior cervical; discectomy and fusion with a interbody cage	Group 1: cage packed with autograft; Group 2: cage packed with HA/TCP; Group 3: cage packed with HA/TCP and 5 × 10^6 MPCs; Group 4: cage packed with HA/TCP and 10 × 10^6 MPCs; Group 5: controls	(i) No significant differences were found between groups 3 and 4; (ii) CT scan showed that 9/12 (75%) MPC-treated animals had continuous bony bridging compared with 1/6 of group 1 and 2/6 of group 2 (p < 0.019 and p < 0.044, resp.); (iii) By quantitative CT, density of new bone in MPC-treated animals was 121% higher than in group 2 (p < 0.017) and 128% higher than in group 1 (p < 0.0001)	[57]
Pig	BMSCs; (10 × 10^6)	rhBMP-2; (0.6 mg)	Bioresorbable scaffolds made from medical grade poly; (Σ-caprolactone)-20% tricalcium phosphate (mPCL/TCP)	9 months	L2-L3 and L4-L5	Group 1: mPCL/TCP with rhBMP-2; Group 2: mPCL/TCP with BMSCs; Group 3: mPCL/TCP; Group 4: autograft	(i) The mean radiographic scores were 3.0, 1.7, 1.0, and 1.8 for groups 1 to 4, respectively; (ii) The bone volume fraction of group 1 was twofold higher than group 2; (iii) Histology, µ-CT, and biomechanical evaluation showed solid and comparable fusion between groups 1 and 4; (iv) Group 2 showed inferior quality of fusion when compared with groups 1 and 4 while group 3 showed no fusion even at 9 months	[58]
Ovine	Autogenous whole BM or BM concentrate	None	TCP	6 months	L4-L5	Group 1: autograft; Group 2: TCP with BM concentrate; Group 3: TCP with whole bone marrow/; Group 4: TCP; .	(i) At 6 months, 33% of group 2 and 25% of the group 1 sites were fused, compared with 8% of group 3 and 0% of group 4; (ii) Histology of fused samples showed denser bone formation in group 2 than in group 1 sites	[59]