title: Integrin-specific hydrogels functionalized with VEGF for vascularization and bone regeneration of critical-size bone defects.
abstract: Vascularization of bone defects is considered a crucial component to the successful regeneration of large bone defects. Although vascular endothelial growth factor (VEGF) has been delivered to critical-size bone defect models to augment blood vessel infiltration into the defect area, its potential to increase bone repair remains ambiguous. In this study, we investigated whether integrin-specific biomaterials modulate the effects of VEGF on bone regeneration. We engineered protease-degradable, VEGF-loaded poly(ethylene glycol) (PEG) hydrogels functionalized with either a triple-helical, α2 β1 integrin-specific peptide GGYGGGP(GPP)5 GFOGER(GPP)5 GPC (GFOGER) or an αv β3 integrin-targeting peptide GRGDSPC (RGD). Covalent incorporation of VEGF into the PEG hydrogel allowed for protease degradation-dependent release of the protein while maintaining VEGF bioactivity. When applied to critical-size segmental defects in the murine radius, GFOGER-functionalized VEGF-free hydrogels exhibited significantly increased vascular volume and density and resulted in a larger number of thicker blood vessels compared to RGD-functionalized VEGF-free hydrogels. VEGF-loaded RGD hydrogels increased vascularization compared to VEGF-free RGD hydrogels, but the levels of vascularization for these VEGF-containing RGD hydrogels were similar to those of VEGF-free GFOGER hydrogels. VEGF transiently increased bone regeneration in RGD hydrogels but had no effect at later time points. In GFOGER hydrogels, VEGF did not show an effect on bone regeneration. However, VEGF-free GFOGER hydrogels resulted in increased bone regeneration compared to VEGF-free RGD hydrogels. These findings demonstrate the importance of integrin-specificity in engineering constructs for vascularization and associated bone regeneration.
authors.affiliation: Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia.|Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: José R
authors.initials: JR
authors.lastname: García
authors.affiliation: Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia.|Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Amy Y
authors.initials: AY
authors.lastname: Clark
authors.affiliation: Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia.|Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Andrés J
authors.initials: AJ
authors.lastname: García
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism*; D001861:Bone Regeneration / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020100:Hydrogels / Q000737:chemistry / Q000378:metabolism*; D038982:Integrin alpha2beta1 / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism*; D011884:Radius / Q000293:injuries / Q000502:physiology; D012212:Rheology; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D001672:Biocompatible Materials; D020100:Hydrogels; D038982:Integrin alpha2beta1; D039302:Integrin alphaVbeta3; D010455:Peptides; D042461:Vascular Endothelial Growth Factor A; D011092:Polyethylene Glycols
keywords: cell adhesion; mesenchymal stem cells; vascularization