title: Vascular endothelial growth factor gene-activated matrix (VEGF165-GAM) enhances osteogenesis and angiogenesis in large segmental bone defects.
abstract: Healing of fractures is dependent on vascularization of bone, which is in turn promoted by VEGF. It was shown that 0.1 and 1 mg of pVEGF165-GAM led to a significant increase in vascularization and bone regeneration in defects that would otherwise have led to atrophic nonunions.
  
  
  BACKGROUND
  One reason for lack of bone healing in nonunions is the absence of vascularization. In skeletogenesis, which is tightly linked to angiogenesis, vascular endothelial growth factor (VEGF) promotes the vascularization of the growth plate and transformation of cartilage to bone. We postulate that a gene-activated matrix (GAM), created with a plasmid coding for human VEGF165, coated on a collagen sponge could efficiently accelerate bone healing in large segmental defects.
  
  
  METHODS
  Sixty New Zealand white rabbits received a 15-mm critical size defect on one radius, which was filled with either 0.1 or 1 mg plasmid-DNA as GAM. Radiographs were obtained every 3 weeks. After 6 or 12 weeks, animals were killed. New bone was measured by microCT scans. Vascularity was measured using anti-CD31 staining of endothelial cells in 18 regions of interest per implant.
  
  
  RESULTS
  Scaffold and control plasmid showed no defect healing, whereas most of the animals in the VEGF groups showed partial or total bone regeneration. Significantly more bone was found in the VEGF groups, with no significant differences between the 0.1- and 1-mg groups. Immunohistochemical staining of endothelial cells revealed that the VEGF groups showed two to three times the number of vessels and a significantly larger endothelial area after 6 weeks. Twelve weeks after surgery, the amount of vascularization decreased, whereas more new bone was detectable.
  
  
  CONCLUSIONS
  The rabbit critical size defect was appropriate in size to produce atrophic nonunions. We showed that angiogenesis and osteogenesis can be promoted by a VEGF165-GAM that is an appropriate tool to induce bone healing in atrophic nonunions.
authors.affiliation: Department of Orthopaedic Surgery, University of Heidelberg, Heidelberg, Germany. florian.geiger@urz.uni-heidelberg.de
authors.forename: Florian
authors.initials: F
authors.lastname: Geiger
authors.forename: Helge
authors.initials: H
authors.lastname: Bertram
authors.forename: Irina
authors.initials: I
authors.lastname: Berger
authors.forename: Helga
authors.initials: H
authors.lastname: Lorenz
authors.forename: Olga
authors.initials: O
authors.lastname: Wall
authors.forename: Christina
authors.initials: C
authors.lastname: Eckhardt
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Simank
authors.forename: Wiltrud
authors.initials: W
authors.lastname: Richter
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D017102:Fracture Healing / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011817:Rabbits; D011884:Radius / Q000098:blood supply / Q000473:pathology; D011885:Radius Fractures / Q000503:physiopathology / Q000628:therapy*; D011994:Recombinant Proteins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology*
chemical_list: D017077:Culture Media, Conditioned; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A