Poly(lactic-co-glycolide) polymer constructs cross-linked with human BMP-6 and VEGF protein significantly enhance rat mandible defect repair

Das, Ashim; Fishero, Brian A.; Christophel, J. Jared; Li, Ching-Ju; Kohli, Nikita; Lin, Yong; Dighe, Abhijit S.; Cui, Quanjun

doi:10.1007/s00441-015-2301-x

Cited by 30 publications

(23 citation statements)

References 46 publications

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“…16–19 However, when we delivered VEGF and BMP-6 to a criticalsized rat mandibular defect, substantial bone regeneration was not achieved and the new bone was poor quality. 20 …”

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confidence: 99%

Assessment of Hedgehog Signaling Pathway Activation for Craniofacial Bone Regeneration in a Critical-Sized Rat Mandibular Defect

Miller

McColl

Arul

et al. 2019

JAMA Facial Plast Surg

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IMPORTANCE Osseous craniofacial defects are currently reconstructed with bone grafting, rigid fixation, free tissue transfer, and/or recombinant human bone morphogenetic protein 2. Although these treatment options often have good outcomes, they are associated with substantial morbidity, and many patients are not candidates for free tissue transfer. OBJECTIVE To assess whether polysaccharide-based scaffold (PS) constructs that are cross-linked with smoothened agonist (SAG), vascular endothelial growth factor (VEGF), and bone morphogenetic protein 6 (BMP-6) would substantially increase bone regeneration. DESIGN, SETTING, AND PARTICIPANTS This animal model study was conducted at the University of Virginia School of Medicine Cui Laboratory from March 1, 2017, to June 30, 2017. Thirty-three 10-week-old female Lewis rats were acquired for the study. Bilateral nonsegmental critical-sized defects were created in the angle of rat mandibles. The defects were either left untreated or filled with 1 of the 9 PSs. The rats were killed after 8 weeks, and bone regeneration was evaluated using microcomputed tomographic imaging and mechanical testing. Analysis of variance testing was used to compare the treatment groups. MAIN OUTCOMES AND MEASURES Blinded analysis and computer analysis of the microcomputed tomographic images were used to assess bone regeneration. RESULTS In the 33 female Lewis rats, minimal healing was observed in the untreated mandibles. Addition of SAG was associated with increases in bone regeneration and bone density in all treatment groups, and maximum bone healing was seen in the group with BMP-6, VEGF, and SAG cross-linked to PS. For each of the 5 no scaffold group vs BMP-6, VEGF, and SAG cross-linked to PS group comparisons, mean defect bone regeneration was 4.14% (95% CI, 0.94%−7.33%) vs 66.19% (95% CI, 54.47%−77.90%); mean bone volume, 14.52 mm3 (95% CI, 13.07–15.97 mm3) vs 20.87 mm3 (95% CI, 14.73– 27.01 mm3); mean bone surface, 68.97 mm2 (95% CI, 60.08–77.85 mm2) vs 96.77 mm2 (95% CI, 76.11–117.43 mm2); mean ratio of bone volume to total volume, 0.11 (95% CI, 0.10–0.11) vs 0.15 (95% CI, 0.10–0.19); and mean connectivity density 0.03 (95% CI, 0.02–0.05) vs 0.32 (95% CI, 0.25–0.38). On mechanical testing, mandibles with untreated defects broke with less force than control mandibles in which no defect was made, although this force did not reach statistical significance. No significant difference in force to fracture was observed among the treatment groups. CONCLUSIONS AND RELEVANCE In this rat model study, activation of the hedgehog signaling pathway using smoothened agonist was associated with increased craniofacial bone regeneration compared with growth factors alone, including US Food and Drug Administration–approved recombinant human bone morphogenetic protein 2. Pharmaceuticals that target this pathway may offer a new reconstructive option for bony craniofacial defects as well as nonunion and delayed healing fractures.

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“…16–19 However, when we delivered VEGF and BMP-6 to a criticalsized rat mandibular defect, substantial bone regeneration was not achieved and the new bone was poor quality. 20 …”

mentioning

confidence: 99%

Assessment of Hedgehog Signaling Pathway Activation for Craniofacial Bone Regeneration in a Critical-Sized Rat Mandibular Defect

Miller

McColl

Arul

et al. 2019

JAMA Facial Plast Surg

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“…To elucidate the role of exogenously added VEGF and BMP-6 in the absence of exogenously added MSCs to enhance bone repair, we cross-linked PLAGA scaffolds to either VEGF or BMP-6, or both growth factors combined, and delivered the PLAGA-growth factor constructs to critical-sized mandibular defects in rats. Significant bone regeneration was observed only in the rats that received the scaffolds to which the combination of VEGF and BMP-6 were cross-linked (Das et al, 2014;submitted for publication). This shows that the presence of extracellular VEGF or BMP-6 alone is not sufficient to enhance osteogenesis, whereas the combined presence of VEGF and BMP-6 is likely to be beneficial for fracture repair.…”

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confidence: 99%

Cross‐Talk Between VEGF and BMP‐6 Pathways Accelerates Osteogenic Differentiation of Human Adipose‐Derived Stem Cells

Madhu

Balian

et al. 2015

Journal Cellular Physiology

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Deficiency in vascular endothelial growth factor (VEGF) or bone morphogenetic proteins (BMPs) results in fracture non-unions. Therefore, it is indispensable to comprehend the combined effect of VEGF and BMPs on the osteogenic differentiation of osteoprogenitor mesenchymal stem cells (MSCs) that are either naturally occurring at the fracture repair site or exogenously added to enhance the bone repair. We found that the combination of VEGF and BMP-6 enhanced COL1A2 expression, which correlated with upregulated expression of osterix, Dlx5, and Msx2 in human adipose-derived stem cells (hADSCs). Cross-talk between VEGF and BMP-6 pathways upregulated activation of p38 mitogen-activated kinase (p38 MAPK) and inhibited activation of protein kinase B (PKB, also known as Akt), whereas phosphorylation of "mothers against decapentaplegic" homologs 1/5/8 (Smads 1/5/8) and extracellular signal-regulated kinases 1 and 2 (ERK 1/2) was not affected. Consistent with these findings, p38 inhibitor SB203580, or siRNA knockdown of osterix, abrogated crosstalk between the VEGF and BMP-6 pathways and significantly reduced the observed upregulation of COL1A2. Nuclear translocation of the phosphorylated form of osterix was also inhibited by SB203580. Although crosstalk between the VEGF-BMP-6 pathways did not show an effect on the extent of mineralization, inhibition of any one of the three components that were upregulated through the cross-talk, i.e., osterix, Dlx5, and p38 activation, led to a complete inhibition of mineralization. Inhibition of PKB/Akt activation, which is attenuated through the cross-talk, significantly enhanced ALP gene expression. These observations imply that crosstalk between the VEGF and BMP-6 signaling pathways enhances osteogenic differentiation of MSCs.

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“…Few studies also tested the combination of VEGF with BMPs and demonstrated their synergistic effects during bone repair/regeneration (Curtin, Tierney, McSorley, Cryan & Duffy, ; Das, Fishero, Christophel, Li & Kohli, ; Peng, Usas, Olshanski, Ho & Gearhart, ). Conversely, other authors showed that the simultaneous release of BMP‐2 and VEGF did not increase bone formation over BMP‐2 alone (Patel et al., ; Young et al., ) or in comparison to a DBBM graft (Schmitt, Lutz, Doering, Lell & Ratky, ) and did not increase de novo bone formation when added to DBBM blocks (Schmitt et al., ).…”

Section: Resultsmentioning

confidence: 99%

The use of bioactive factors to enhance bone regeneration: A narrative review

Donos

Dereka

Calciolari

2019

J Clinic Periodontology

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Aim This review critically appraises the available knowledge on the pre‐clinical and clinical use of bioactive factors for bone regeneration in the cranial and maxillofacial area. Materials and Methods The use of growth factors, amelogenins and autologous platelet concentrates (APCs) for bone regeneration was reviewed in a systematic manner. More specifically, pre‐clinical and clinical studies on ridge preservation, alveolar ridge augmentation, regeneration of peri‐implant defects and sinus augmentation models were considered. Results Amongst different bioactive factors, the highest pre‐clinical and clinical evidence of a positive effect on bone formation is associated with rhBMP‐2 and the lowest with amelogenins. While APCs seem to accelerate clinical healing and reduce postoperative discomfort, there is insufficient and contrasting evidence of a significant effect on hard tissue regeneration for the different clinical applications. Conclusions Although there is increasing evidence that bioactive factors might enhance the bone regeneration process, the great heterogeneity of the available studies and the limited number of RCTs do not allow to draw robust conclusions. Issues that still need to be investigated include the optimal carriers for bioactive agents (direct vs. indirect), the dosage, the timing of administration, as well as the possibility of combining different agents to promote synergistic effects.

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Poly(lactic-co-glycolide) polymer constructs cross-linked with human BMP-6 and VEGF protein significantly enhance rat mandible defect repair

Cited by 30 publications

References 46 publications

Assessment of Hedgehog Signaling Pathway Activation for Craniofacial Bone Regeneration in a Critical-Sized Rat Mandibular Defect

Assessment of Hedgehog Signaling Pathway Activation for Craniofacial Bone Regeneration in a Critical-Sized Rat Mandibular Defect

Cross‐Talk Between VEGF and BMP‐6 Pathways Accelerates Osteogenic Differentiation of Human Adipose‐Derived Stem Cells

The use of bioactive factors to enhance bone regeneration: A narrative review

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