title: Enhanced angiogenesis and osteogenesis in critical bone defects by the controlled release of BMP-2 and VEGF: implantation of electron beam melting-fabricated porous Ti6Al4V scaffolds incorporating growth factor-doped fibrin glue.
abstract: Electron beam melting (EBM)-fabricated porous titanium implants possessing low elastic moduli and tailored structures are promising biomaterials for orthopedic applications. However, the bio-inert nature of porous titanium makes reinforcement with growth factors (GFs) a promising method to enhance implant in vivo performance. Bone-morphogenic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) are key factors of angiogenesis and osteogenesis. Therefore, the present study is aimed at evaluating EBM-fabricated porous titanium implants incorporating GF-doped fibrin glue (FG) as composite scaffolds providing GFs for improvement of angiogenesis and osteogenesis in rabbit femoral condyle defects. BMP-2 and VEGF were added into the constituent compounds of FG, and then this GF-doped FG was subsequently injected into the porous scaffolds. In five groups of implants, angiogenesis and osteogenesis were evaluated at 4 weeks post-implantation using Microfil perfusion and histological analysis: eTi (empty scaffolds), cTi (containing undoped FG), BMP/cTi (containing 50 μg rhBMP-2), VEGF/cTi (containing 0.5 μg VEGF) and Dual/cTi (containing 50 μg rhBMP-2 and 0.5 μg VEGF). The results demonstrate that these composite implants are biocompatible and provide the desired gradual release of the bioactive growth factors. Incorporation of GF delivery, whether a single factor or dual factors, significantly enhanced both angiogenesis and osteogenesis inside the porous scaffolds. However, the synergistic effect of the dual factors combination was observable on angiogenesis but absent on osteogenesis. In conclusion, fibrin glue is a biocompatible material that could be employed as a delivery vehicle in EBM-fabricated porous titanium for controlled release of BMP-2 and VEGF. Application of this method for loading a porous titanium scaffold to incorporate growth factors is a convenient and promising strategy for improving osteogenesis of critical-sized bone defects.
authors.affiliation: Department of Orthopedics, Peking University Third Hospital, Beijing 100191, People's Republic of China.
authors.forename: Jia
authors.initials: J
authors.lastname: Lv
authors.forename: Peng
authors.initials: P
authors.lastname: Xiu
authors.forename: Jie
authors.initials: J
authors.lastname: Tan
authors.forename: Zhaojun
authors.initials: Z
authors.lastname: Jia
authors.forename: Hong
authors.initials: H
authors.lastname: Cai
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000497:Alloys; D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001861:Bone Regeneration / Q000187:drug effects; D002470:Cell Survival; D018920:Coculture Techniques; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D055119:Elastic Modulus; D004583:Electrons; D005264:Femoral Fractures / Q000628:therapy; D015718:Fibrin Tissue Adhesive; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008422:Materials Testing; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects*; D016062:Porosity; D019736:Prostheses and Implants; D011817:Rabbits; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D054457:Tissue Scaffolds; D014025:Titanium; D016212:Transforming Growth Factor beta / Q000008:administration & dosage* / Q000493:pharmacokinetics; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000497:Alloys; D001672:Biocompatible Materials; D055396:Bone Morphogenetic Protein 2; D003692:Delayed-Action Preparations; D015718:Fibrin Tissue Adhesive; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C499469:recombinant human bone morphogenetic protein-2; C031462:titanium alloy (TiAl6V4); D014025:Titanium