Continuous delivery of rhBMP2 and rhVEGF165 at a certain ratio enhances bone formation in mandibular defects over the delivery of rhBMP2 alone--An experimental study in rats.
The aim of the present study was to test the hypothesis that different amounts of vascular endothelial growth factor and bone morphogenic protein differentially affect bone formation when applied for repair of non-healing defects in the rat mandible. Porous composite PDLLA/CaCO3 carriers were fabricated as slow release carriers and loaded with rhBMP2 and rhVEGF165 in 10 different dosage combinations using gas foaming with supercritical carbon dioxide. They were implanted in non-healing defects of the mandibles of 132 adult Wistar rats with additional lateral augmentation. Bone formation was assessed both radiographically (bone volume) and by histomorphometry (bone density). The use of carriers with a ratio of delivery of VEGF/BMP between 0.7 and 1.2 was significantly related to the occurrence of significant increases in radiographic bone volume and/or histologic bone density compared to the use of carriers with a ratio of delivery of ≤ 0.5 when all intervals and all outcome parameters were considered. Moreover, simultaneous delivery at this ratio helped to "save" rhBMP2 as both bone volume and bone density after 13 weeks were reached/surpassed using half the dosage required for rhBMP2 alone. It is concluded, that the combined delivery of rhVEGF165 and rhBMP2 for repair of critical size mandibular defects can significantly enhance volume and density of bone formation over delivery of rhBMP2 alone. It appears from the present results that continuous simultaneous delivery of rhVEGF165 and rhBMP2 at a ratio of approximately 1 is favourable for the enhancement of bone formation.
Dept. of Oral and Maxillofacial Surgery, George-Augusta-University, Göttingen, Germany.
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Lohse
Dept. of Oral and Maxillofacial Surgery, George-Augusta-University, Göttingen, Germany.
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Moser
Inorganic Chemistry and Center for Nanointegration Duisburg-Essen (CeNIDE), University of Duisburg-Essen, Universitaetsstr. 5-7, 45117 Essen, Germany.
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Backhaus
Inorganic Chemistry and Center for Nanointegration Duisburg-Essen (CeNIDE), University of Duisburg-Essen, Universitaetsstr. 5-7, 45117 Essen, Germany.
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Annen
Inorganic Chemistry and Center for Nanointegration Duisburg-Essen (CeNIDE), University of Duisburg-Essen, Universitaetsstr. 5-7, 45117 Essen, Germany.
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Epple
Dept. of Oral and Maxillofacial Surgery, George-Augusta-University, Göttingen, Germany. Electronic address: schliephake.henning@med.uni-goettingen.de.
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Schliephake
D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000737:chemistry; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage* / Q000737:chemistry; D002119:Calcium Carbonate / Q000737:chemistry*; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004338:Drug Combinations; D004339:Drug Compounding; D007700:Kinetics; D008297:Male; D008334:Mandible / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology; D010012:Osteogenesis / Q000187:drug effects*; D011091:Polyesters / Q000737:chemistry*; D016062:Porosity; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage; D012995:Solubility; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000737:chemistry; D014945:Wound Healing / Q000187:drug effects*
D043925:Angiogenesis Inducing Agents; C525718:BMP2 protein, human; D050071:Bone Density Conservation Agents; D055396:Bone Morphogenetic Protein 2; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004338:Drug Combinations; D011091:Polyesters; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C033616:poly(lactide); D002119:Calcium Carbonate
Angiogenesis; Bone formation; Bone morphogenic protein; Polymer; Retarded delivery; Vascular endothelial growth factor