title: Dual growth factor delivery from biofunctionalized allografts: Sequential VEGF and BMP-2 release to stimulate allograft remodeling.
abstract: Autografts have been shown to stimulate osteogenesis, osteoclastogenesis, and angiogenesis, and subsequent rapid graft incorporation. Large structural allografts, however, suffer from limited new bone formation and remodeling, both of which are directly associated with clinical failure due to non-unions, late graft fractures, and infections, making it a priority to improve large structural allograft healing. We have previously shown the osteogenic ability of a polymer-coated allograft that delivers bone morphogenetic protein-2 both in vitro and in vivo through both burst release and sustained release kinetics. In this study, we have demonstrated largely sequential delivery of bone morphogenetic protein-2 and vascular endothelial growth factor from the same coated allograft. Release data showed that loading both growth factors onto a polymeric coating with two different techniques resulted in short-term (95% release within 2 weeks) and long-term (95% release within 5 weeks) delivery kinetics. We have also demonstrated how released VEGF, traditionally associated with angiogenesis, can also provide a stimulus for allograft remodeling via resorption. Bone marrow derived mononuclear cells were co-cultured with VEGF released from the coated allograft and showed a statistically significant (p < 0.05) and dose dependent increase in the number of tartrate-resistant acid phosphatase-positive multinucleated osteoclasts. Functionality of these osteoclasts was assessed quantitatively and qualitatively by evaluating resorption pit area from both osteo-assay plates and harvested bone. Data indicated a statistically significant higher resorption area from the cells exposed to VEGF released from the allografts over controls (p < 0.05). These results indicate that by using different loading protocols temporal control can be achieved when delivering multiple growth factors from a polymer-coated allograft. Further, released VEGF can also stimulate osteoclastogenesis that may enhance allograft incorporation, and thus mitigate long-term clinical complications. © 2017 Orthopedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1086-1095, 2017.
authors.affiliation: Department of Materials Science and Engineering, University of Connecticut, Storrs, Connecticut.|Institute for Regenerative Engineering, University of Connecticut Health Center, Farmington, Connecticut.
authors.forename: Farzana
authors.initials: F
authors.lastname: Sharmin
authors.affiliation: Institute for Regenerative Engineering, University of Connecticut Health Center, Farmington, Connecticut.|Department of Biomedical Engineering, University of Connecticut, Storrs, Connecticut.
authors.forename: Casey
authors.initials: C
authors.lastname: McDermott
authors.affiliation: Department of Orthopedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, California.
authors.forename: Jay
authors.initials: J
authors.lastname: Lieberman
authors.affiliation: Department of Orthopedic Surgery, University of Connecticut Health Center, Farmington, Connecticut.|New England Musculoskeletal Institute, University of Connecticut Health Center, Farmington, Connecticut, 06030.
authors.forename: Archana
authors.initials: A
authors.lastname: Sanjay
authors.affiliation: Department of Materials Science and Engineering, University of Connecticut, Storrs, Connecticut.|Institute for Regenerative Engineering, University of Connecticut Health Center, Farmington, Connecticut.|Department of Biomedical Engineering, University of Connecticut, Storrs, Connecticut.|Department of Orthopedic Surgery, University of Connecticut Health Center, Farmington, Connecticut.|New England Musculoskeletal Institute, University of Connecticut Health Center, Farmington, Connecticut, 06030.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Khan
mesh_terms: D064591:Allografts; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage*; D001861:Bone Regeneration / Q000187:drug effects*; D016025:Bone Transplantation; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D008297:Male; D010010:Osteoclasts / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*
chemical_list: D055396:Bone Morphogenetic Protein 2; D042461:Vascular Endothelial Growth Factor A
keywords: allograft; bone morphogenetic protein-2; factor-delivery; osteoclast; vascular endothelial growth factor