Wound Complications Associated With Bone Morphogenetic Protein-2 in Orthopaedic Trauma Surgery

Chan, Daniel Shiu‐Hin; Garland, Joshua; Infante, Anthony; Sanders, Roy; Sagi, H. Claude

doi:10.1097/bot.0000000000000117

Cited by 34 publications

(18 citation statements)

References 14 publications

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“…RhBMP‐2 is traditionally loaded on to a collagen sponge and it has been hypothesized that the rapid release of the Bone Morphogenetic Protein (BMP) from the sponge limits its osteoinductive activity . In order to overcome this limitation, high doses of rhBMP‐2 are used clinically which has been associated with reports of postoperative complications including heterotopic bone formation, soft tissue swelling and osteolysis …”

Section: Introductionmentioning

confidence: 99%

“…[7][8][9] In order to overcome this limitation, high doses of rhBMP-2 are used clinically which has been associated with reports of postoperative complications including heterotopic bone formation, soft tissue swelling and osteolysis. 10,11 3D printed scaffolds represent a promising approach for bone repair. 3D printed scaffolds can be customized to fit complex anatomic skeletal defects.…”

Section: Introductionmentioning

confidence: 99%

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3D printed hyperelastic “bone” scaffolds and regional gene therapy: A novel approach to bone healing

Alluri

Jakus

Bougioukli

et al. 2018

J Biomedical Materials Res

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The purpose of this study was to evaluate the viability of human adipose-derived stem cells (ADSCs) transduced with a lentiviral (LV) vector to overexpress bone morphogenetic protein-2 (BMP-2) loaded onto a novel 3D printed scaffold. Human ADSCs were transduced with a LV vector carrying the cDNA for BMP-2. The transduced cells were loaded onto a 3D printed Hyperelastic "Bone" (HB) scaffold. In vitro BMP-2 production was assessed using enzyme-linked immunosorbent assay analysis. The ability of ADSCs loaded on the HB scaffold to induce in vivo bone formation in a hind limb muscle pouch model was assessed in the following groups: ADSCs transduced with LV-BMP-2, LV-green fluorescent protein, ADSCs alone, and empty HB scaffolds. Bone formation was assessed using radiographs, histology and histomorphometry. Transduced ADSCs BMP-2 production on the HB scaffold at 24 hours was similar on 3D printed HB scaffolds versus control wells with transduced cells alone, and continued to increase after 1 and 2 weeks of culture. Bone formation was noted in LV-BMP-2 animals on plain radiographs at 2 and 4 weeks after implantation; no bone formation was noted in the other groups. Histology demonstrated that the LV-BMP-2 group was the only group that formed woven bone and the mean bone area/tissue area was significantly greater when compared with the other groups. 3D printed HB scaffolds are effective carriers for transduced ADSCs to promote bone repair. The combination of gene therapy and tissue engineered scaffolds is a promising multidisciplinary approach to bone repair with significant clinical potential. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1104-1110, 2018.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

3D printed hyperelastic “bone” scaffolds and regional gene therapy: A novel approach to bone healing

Alluri

Jakus

Bougioukli

et al. 2018

J Biomedical Materials Res

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“…However, the supraphysiologic doses of rhBMP used in clinical practice and the kinetics of BMP release from the carrier [2] are associated with inconsistent clinical results and several complications [3,4,5]. Previous animal studies using a mouse critical-sized femoral defect model in our laboratory have demonstrated that treatment with rhBMP-2 leads to healing of the defect, with the bony bridge gradually becoming thinner at later time points (28 and 56 days after treatment) [6].…”

Section: Introductionmentioning

confidence: 99%

Combination therapy with BMP-2 and a systemic RANKL inhibitor enhances bone healing in a mouse critical-sized femoral defect

Bougioukli

Jain

Sugiyama

et al. 2016

Bone

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Recombinant human BMP-2 (rhBMP-2) is a potent osteoinductive agent, but has been associated not only with bone formation, but also osteoclastogenesis and bone resorption. Osteoprotegerin (OPG) is a RANKL inhibitor that blocks differentiation and function of osteoclasts. We hypothesized that the combination of local BMP-2 (recombinant protein or a product of gene therapy) plus systemic OPG-Fc is more effective than BMP-2 alone in promoting bone repair. To test this hypothesis we used a mouse critical-sized femoral defect model. Col2.3eGFP (osteoblastic marker) male mice were treated with rhBMP-2 (group I), rhBMP-2 and systemic OPG (group II), rhBMP-2 and delayed administration of OPG (group III), mouse BM cells transduced with a lentiviral vector containing the BMP-2 gene (LV-BMP-2; group IV), LV-BMP-2 and systemic OPG (group V), a carrier alone (group VI) and administration of OPG alone (group VII). All bone defects treated with BMP-2 (alone or combined with OPG) healed, whereas minimal bone formation was noted in animals treated with the carrier alone or OPG alone. MicroCT analysis showed that bone volume (BV) in rhBMP-2 + OPG and LV-BMP-2 + OPG groups was significantly higher compared to rhBMP-2 alone (p < 0.01) and LV-BMP-2 alone (p < 0.001). Similar results were observed in histomorphometry, with rhBMP-2 alone defects exhibiting significantly lower bone area (B.Ar) compared to rhBMP-2 + OPG defects (p < 0.005) and LV-BMP-2 defects having a significantly lower B.Ar compared to all BMP-2 + OPG treated groups (p ≤ 0.01). TRAP staining demonstrated a major osteoclast response in the groups that did not receive OPG (rhBMP-2, LV-BMP-2 and sponge alone) beginning as early as 7 days post-operatively. In conclusion, we demonstrated that locally delivered BMP-2 (recombinant protein or gene therapy) in combination with systemically administered OPG improved bone healing compared to BMP-2 alone in a mouse critical-sized bone defect. These data indicate that osteoclasts can diminish healing responses to BMP-2 and that RANKL inhibition may thus accentuate BMP-2 efficacy.

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“…78 Likewise, Chan et al found significantly higher wound complication rates among the rhBMP-2 treatment group (31%) than among the control group (18%). 79 Further analysis of complications in posterior fusion surgeries illustrates a fivefold increase (2.1% vs. 0.4%) in wound complications associated with BMP-2 use during a posterior approach. 80 Infections, both local and systemic, are known complications of all invasive procedures.…”

Section: Wound Complications With Bmp-2mentioning

confidence: 99%

A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2

James

LaChaud

Shen

et al. 2016

Tissue Engineering Part B: Reviews

823

769

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Bone morphogenetic protein-2 (BMP-2) is currently the only Food and Drug Administration (FDA)-approved osteoinductive growth factor used as a bone graft substitute. However, with increasing clinical use of BMP-2, a growing and well-documented side effect profile has emerged. This includes postoperative inflammation and associated adverse effects, ectopic bone formation, osteoclast-mediated bone resorption, and inappropriate adipogenesis. Several large-scale studies have confirmed the relative frequency of adverse events associated with the clinical use of BMP-2, including life-threatening cervical spine swelling. In fact, the FDA has issued a warning of the potential life-threatening complications of BMP-2. This review summarizes the known adverse effects of BMP-2, including controversial areas such as tumorigenesis. Next, select animal models that replicate BMP-2's adverse clinical effects are discussed. Finally, potential molecules to mitigate the adverse effects of BMP-2 are reviewed. In summary, BMP-2 is a potent osteoinductive cytokine that has indeed revolutionized the bone graft substitute market; however, it simultaneously has accrued a worrisome side effect profile. Better understanding of these adverse effects among both translational scientists and clinicians will help determine the most appropriate and safe use of BMP-2 in the clinical setting.

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Wound Complications Associated With Bone Morphogenetic Protein-2 in Orthopaedic Trauma Surgery

Abstract: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Cited by 34 publications

References 14 publications

3D printed hyperelastic “bone” scaffolds and regional gene therapy: A novel approach to bone healing

3D printed hyperelastic “bone” scaffolds and regional gene therapy: A novel approach to bone healing

Combination therapy with BMP-2 and a systemic RANKL inhibitor enhances bone healing in a mouse critical-sized femoral defect

A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2

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