Abstract
IntroductionCell-based therapy by bone marrow mononuclear cells (BMC) in a large-sized bone defect has already shown improved vascularization and new bone formation. First clinical trials are already being conducted. BMC were isolated from bone marrow aspirate and given back to patients in combination with a scaffold within some hours. However, the optimal concentration of BMC has not yet been determined for bone healing. With this study, we want to determine the optimal dosage of the BMC in the bone defect to support bone healing.Material and methodsScaffolds with increasing BMC concentrations were inserted into a 5 mm femoral defect, cell concentrations of 2 × 106 BMC/mL, 1 × 107 BMC/mL and 2 × 107 BMC/mL were used. Based on the initial cell number used to colonize the scaffolds, the groups are designated 1 × 106, 5 × 106 and 1 × 107 group. Bone healing was assessed biomechanically, radiologically (µCT), and histologically after 8 weeks healing time.ResultsImproved bone healing parameters were noted in the 1 × 106 and 5 × 106 BMC groups. A significantly higher BMD was observed in the 1 × 106 BMC group compared to the other groups. Histologically, a significantly increased bone growth in the defect area was observed in group 5 × 106 BMC. This finding could be supported radiologically.ConclusionIt was shown that the effective dose of BMC for bone defect healing ranges from 2 × 106 BMC/mL to 1 × 107 BMC/mL. This concentration range seems to be the therapeutic window for BMC-supported therapy of large bone defects. However, further studies are necessary to clarify the exact BMC-dose dependent mechanisms of bone defect healing and to determine the therapeutically effective range more precisely.
Highlights
Cell-based therapy by bone marrow mononuclear cells (BMC) in a large-sized bone defect has already shown improved vascularization and new bone formation
Several types of cells with regenerative potential like precursors of marrow stromal cells (MSC), hematopoietic stem cells (HSC) as a putative source of endothelial progenitor cells (EPC), and monocytes were found [8, 10,11,12,13] Our own previous work demonstrated that BMCs seeded on uncoated β-tricalcium phosphate (β-TCP) scaffolds [8] (1.3 × 106 BMC/mL) and transplanted into an experimental femur defect, exerted highly beneficial effects on the bone healing response [14, 15] qualitatively comparable to those mediated by cultured MSC and EPC [2, 3]
In our own recently completed phase-I clinical study, we demonstrated that BMC seeded onto pre-implanted β-TCP scaffold in a bone defect was well tolerated and complete bone healing was achieved in all 10 patients after 3 months [9]
Summary
Cell-based therapy by bone marrow mononuclear cells (BMC) in a large-sized bone defect has already shown improved vascularization and new bone formation. A significantly increased bone growth in the defect area was observed in group 5 × 106 BMC Several types of cells with regenerative potential like precursors of MSC, hematopoietic stem cells (HSC) as a putative source of EPC, and (immature) monocytes were found [8, 10,11,12,13] Our own previous work demonstrated that BMCs seeded on uncoated β-TCP scaffolds [8] (1.3 × 106 BMC/mL) and transplanted into an experimental femur defect, exerted highly beneficial effects on the bone healing response [14, 15] qualitatively comparable to those mediated by cultured MSC and EPC [2, 3]. In our own recently completed phase-I clinical study, we demonstrated that BMC seeded onto pre-implanted β-TCP scaffold in a bone defect was well tolerated and complete bone healing was achieved in all 10 patients after 3 months [9]
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