title: VEGF incorporated into calcium phosphate ceramics promotes vascularisation and bone formation in vivo.
abstract: Bone formation and osseointegration of biomaterials are dependent on angiogenesis and vascularization. Angiogenic growth factors such as vascular endothelial growth factor (VEGF) were shown to promote biomaterial vascularization and enhance bone formation. However, high local concentrations of VEGF induce the formation of malformed, nonfunctional vessels. We hypothesized that a continuous delivery of low concentrations of VEGF from calcium phosphate ceramics may increase the efficacy of VEGF administration.VEGF was co-precipitated onto biphasic calcium phosphate (BCP) ceramics to achieve a sustained release of the growth factor. The co-precipitation efficacy and the release kinetics of the protein were investigated in vitro. For in vivo investigations BCP ceramics were implanted into critical size cranial defects in Balb/c mice. Angiogenesis and microvascularization were investigated over 28 days by means of intravital microscopy. The formation of new bone was determined histomorphometrically. Co-precipitation reduced the burst release of VEGF. Furthermore, a sustained, cell-mediated release of low concentrations of VEGF from BCP ceramics was mediated by resorbing osteoclasts. In vivo, sustained delivery of VEGF achieved by protein co-precipitation promoted biomaterial vascularization, osseointegration, and bone formation. Short-term release of VEGF following superficial adsorption resulted in a temporally restricted promotion of angiogenesis and did not enhance bone formation. The release kinetics of VEGF appears to be an important factor in the promotion of biomaterial vascularization and bone formation. Sustained release of VEGF increased the efficacy of VEGF delivery demonstrating that a prolonged bioavailability of low concentrations of VEGF is beneficial for bone regeneration.
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Wernike
authors.forename: M-O
authors.initials: MO
authors.lastname: Montjovent
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: D
authors.initials: D
authors.lastname: Wismeijer
authors.forename: E B
authors.initials: EB
authors.lastname: Hunziker
authors.forename: K-A
authors.initials: KA
authors.lastname: Siebenrock
authors.forename: W
authors.initials: W
authors.lastname: Hofstetter
authors.forename: F M
authors.initials: FM
authors.lastname: Klenke
mesh_terms: D000818:Animals; D001672:Biocompatible Materials; D001808:Blood Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001847:Bone Diseases / Q000628:therapy; D001861:Bone Regeneration / Q000187:drug effects* / Q000502:physiology; D018786:Bone Substitutes / Q000737:chemistry / Q000494:pharmacology; D001842:Bone and Bones / Q000098:blood supply / Q000187:drug effects / Q000601:surgery; D002130:Calcium Phosphates / Q000737:chemistry* / Q000627:therapeutic use; D002478:Cells, Cultured; D002516:Ceramics / Q000737:chemistry* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D020007:Implants, Experimental; D015918:Infusion Pumps, Implantable / Q000639:trends; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D016348:Osseointegration / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D019736:Prostheses and Implants / Q000639:trends; D019919:Prosthesis Implantation / Q000379:methods; D012886:Skull / Q000033:anatomy & histology / Q000098:blood supply / Q000601:surgery; D023822:Tissue Engineering; D054457:Tissue Scaffolds; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001672:Biocompatible Materials; D018786:Bone Substitutes; D002130:Calcium Phosphates; D042461:Vascular Endothelial Growth Factor A; C020243:calcium phosphate