title: Induction of angiogenesis and osteogenesis in surgically revascularized frozen bone allografts by sustained delivery of FGF-2 and VEGF.
abstract: Large conventional bone allografts are susceptible to fracture and nonunion due to incomplete revascularization and insufficient bone remodeling. We aim to improve bone blood flow and bone remodeling using surgical angiogenesis combined with delivery of fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF). Frozen femoral allografts were heterotopically transplanted in a rat model. The saphenous arteriovenous bundle was implanted within the graft medullary canal. Simultaneously, biodegradable microspheres containing phosphate buffered saline (control), FGF-2, VEGF, or FGF-2 + VEGF were placed within the graft. Rats were sacrificed at 4 and 18 weeks. Angiogenesis was determined by quantifying bone capillary density and measuring cortical bone blood flow. Bone remodeling was assessed by histology, histomorphometry, and alkaline phosphatase activity. VEGF significantly increased angiogenesis and bone remodeling at 4 and 18 weeks. FGF-2 did not elicit a strong angiogenic or osteogenic response. No synergistic effect of FGF-2 + VEGF was observed. VEGF delivered in microspheres had superior long-term effect on angiogenesis and osteogenesis in surgically revascularized frozen bone structural allografts as compared to FGF-2 or FGF-2 + VEGF. Continuous and localized delivery of VEGF by microencapsulation has promising clinical potential by inducing a durable angiogenic and osteogenic response in frozen allografts.
authors.affiliation: Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Wouter F
authors.initials: WF
authors.lastname: Willems
authors.forename: Mikko
authors.initials: M
authors.lastname: Larsen
authors.forename: Patricia F
authors.initials: PF
authors.lastname: Friedrich
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Shogren
authors.forename: Allen T
authors.initials: AT
authors.lastname: Bishop
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D016025:Bone Transplantation; D002196:Capillaries / Q000187:drug effects; D004339:Drug Compounding; D005260:Female; D005269:Femur / Q000098:blood supply / Q000201:enzymology / Q000637:transplantation; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010011:Osteocytes / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D014184:Transplantation, Homologous; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*; D014656:Vascular Surgical Procedures
chemical_list: D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D000469:Alkaline Phosphatase