Enhancement of posterolateral lumbar spine fusion using low‐dose rhBMP‐2 and cultured marrow stromal cells

Abstract

We tested the hypothesis that the dose of recombinant human bone morphogenetic protein-2 (rhBMP-2) required to induce spine fusion can be reduced by combination with mesenchymal stem cells (MSCs). Twenty-four adult rabbits underwent posterolateral intertransverse fusion at the L4-L5 level. The animals were divided into four groups based on the implant material: autologous iliac graft, Alginate-MSCs composite, Alginate-BMP-2-MSCs composite, and Alginate-BMP-2 composite. After 16 weeks, the rabbits were euthanized for radiographic examination, manual palpation, biomechanical testing, and histology. Radiographic union of 12 intertransverse fusion areas for the autogenous iliac graft, Alginate-MSCs, Alginate-BMP-2-MSCs, and Alginate-BMP-2 groups was 11, 8, 11, and 0, respectively. Moreover, manual palpation of six fusion segments in each subgroup found solid union to be 6, 1, 5, and 0, respectively. The average torques at failure of the first three groups were 2278 AE 135, 1943 AE 140, and 2334 AE 187 N-mm, respectively. The failure torque did not differ significantly between the autograft and Alginate-BMP-2-MSCs groups; both groups were significantly higher than the Alginate-MSCs group. The results indicate that MSCs delivered with in vitro cellular doses of rhBMP-2 are more osteoinductive than MSCs without rhBMP-2. In combination with MSCs, a low dose (2.5 mg) of rh-BMP-2 could enhance bone formation and posterolateral spine fusion success in the rabbit model. 1-4 However, limitations exist in related clinical applications, including the inconsistent fusion rate and the high cost associated with the high dosage required for osteoinductive factors.During the recent decade, numerous investigators have described techniques for isolating human and animal mesenchymal stem cells (MSCs) from bone marrow.5-7 Culturing MSCs with dexamethasone, ascorbic acid, and b-glycerophosphate directs the cells into the osteogenic lineage.6,7 Additionally, recombinant human bone morphogenetic proteins (rhBMP) were reported to enhance the osteogenic potency of MSCs. 8,9 Theoretically, low-dose rhBMP-2 can improve the osteogenic potency of preconditioned MSCs and can then be used to improve the success of spinal fusion.We tested the hypothesis that rhBMP-2 can enhance the osteogenic potency of preconditioned MSCs and that the dosage of rhBMP-2 to induce intertransverse spine fusion could be lower than previously required.

Genetically Modified Mesenchymal Stem Cells Induce Mechanically Stable Posterior Spine Fusion

“…In the presence of a potent osteogenic inducer, such as BMP, MSCs can accelerate bone formation and lead to spine fusion. This can be achieved either by culturing MSCs in the presence of BMP and then transplanting them 35 or by overexpressing the gene encoding for BMP-2 in the implanted cells. The latter approach has the advantage of a sustained secretion of BMP in vivo, affecting both host and the implanted cells, in a synergistic autocrine/paracrine mechanism.…”

Tissue engineered bone using select growth factors: A comprehensive review of animal studies and clinical translation studies in man

“…Small animal models included mouse (Yu et al, 2010b), rabbit and rat . Bone defects investigated included both endochondral and intramembranous bone segmental defects Kirker-Head et al, 1998;, lumbar fusions (Akamaru et al, 2003;Fu et al, 2009) and drill defects (He et al, 2009;Levi et al, 2010), in addition to ectopic implants intramuscularly (Luca et al, 2010b;Saito et al, 2003) and subcutaneously (Fu et al, 2010;Kimura et al, 2010). Consequently, it may be more informative for authors to reference concentration and volume within given defect dimensions rather than a simple dosage as a standard between models.…”

Titanium and tantalum as mesenchymal stem cell scaffolds for spinal fusion: an in vitro comparative study

“…For all those reasons, they are extensively assessed in musculoskeletal research [14,16,21]. In this regard, they have been tested for spinal fusion [10,11,13,15,18] or for bone defects treatment [17]. In the latter manuscript, a calcium phosphate scaffold was used.…”