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Abstract Healing of bone defects represents a profound clinical challenge due to limited efficiency of available treatments. Enhancement of endogenous mesenchymal stem cells (MSCs) mobilization and homing is a novel proposed approach for the improvement of bone tissue repair. The present study tested the hypothesis that systemic mobilization by Substance P (SP) and/or local homing by stromal cell derived factor-1α (SDF-1α) can augment suboptimal dose of recombinant human bone morphogenetic protein-2 (rhBMP-2) induced ectopic bone formation in a rat model. Rats received two intravenous injections of either saline or SP at operation day as well as on postoperative day 1 of the subcutaneous implantation of absorbable collagen sponges (ACS’s). The sponges were loaded with saline or suboptimal dose of rhBMP-2 or the combination of suboptimal dose of rhBMP-2 and SDF-1α. At 28 days, bone formation in the explanted scaffolds was assessed biochemically by ALP colorimetric and OPN ELISA assays, radiologically by microcomputed tomography (µCT) as well as histologically. SDF-1α had no statistically significant effect on ALP activity. Similarly, SDF-1α had no statistically significant effect on bone volume (BV) and bone mineral content (BMC) compared with rhBMP loaded ASC’s. However, TMD was significantly increased with SDF-1α and histology revealed more active bone formation. The addition of SP treatment solely or combined with SDF-1α had a statistically significant stimulatory effect on ALP activity, TMD, BV and BMC compared with rhBMP loaded ASC’s, with the higher results observed in the combined treatment group (group V). Histology was consistent with biochemistry and radiology results showing more mature bone formation. OPN assay showed an OPN level that was equal in all study groups. |