title: Bone regeneration using an alpha 2 beta 1 integrin-specific hydrogel as a BMP-2 delivery vehicle.
abstract: Non-healing bone defects present tremendous socioeconomic costs. Although successful in some clinical settings, bone morphogenetic protein (BMP) therapies require supraphysiological dose delivery for bone repair, raising treatment costs and risks of complications. We engineered a protease-degradable poly(ethylene glycol) (PEG) synthetic hydrogel functionalized with a triple helical, α2β1 integrin-specific peptide (GFOGER) as a BMP-2 delivery vehicle. GFOGER-functionalized hydrogels lacking BMP-2 directed human stem cell differentiation and produced significant enhancements in bone repair within a critical-sized bone defect compared to RGD hydrogels or empty defects. GFOGER functionalization was crucial to the BMP-2-dependent healing response. Importantly, these engineered hydrogels outperformed the current clinical carrier in repairing non-healing bone defects at low BMP-2 doses. GFOGER hydrogels provided sustained in vivo release of encapsulated BMP-2, increased osteoprogenitor localization in the defect site, enhanced bone formation and induced defect bridging and mechanically robust healing at low BMP-2 doses which stimulated almost no bone regeneration when delivered from collagen sponges. These findings demonstrate that GFOGER hydrogels promote bone regeneration in challenging defects with low delivered BMP-2 doses and represent an effective delivery vehicle for protein therapeutics with translational potential.
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, GA 30332, USA; Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332, USA.
authors.forename: Asha
authors.initials: A
authors.lastname: Shekaran
authors.affiliation: Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332, USA; School of Mechanical Engineering, Georgia Institute of Technology, 801 Ferst Drive, Atlanta, GA 30332, USA.
authors.forename: José R
authors.initials: JR
authors.lastname: García
authors.affiliation: Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332, USA; School of Mechanical Engineering, Georgia Institute of Technology, 801 Ferst Drive, Atlanta, GA 30332, USA.
authors.forename: Amy Y
authors.initials: AY
authors.lastname: Clark
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, GA 30332, USA.
authors.forename: Taylor E
authors.initials: TE
authors.lastname: Kavanaugh
authors.affiliation: Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332, USA; School of Mechanical Engineering, Georgia Institute of Technology, 801 Ferst Drive, Atlanta, GA 30332, USA.
authors.forename: Angela S
authors.initials: AS
authors.lastname: Lin
authors.affiliation: Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332, USA; School of Mechanical Engineering, Georgia Institute of Technology, 801 Ferst Drive, Atlanta, GA 30332, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Guldberg
authors.affiliation: Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332, USA; School of Mechanical Engineering, Georgia Institute of Technology, 801 Ferst Drive, Atlanta, GA 30332, USA. Electronic address: andres.garcia@me.gatech.edu.
authors.forename: Andrés J
authors.initials: AJ
authors.lastname: García
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics* / Q000378:metabolism; D001861:Bone Regeneration / Q000187:drug effects* / Q000502:physiology; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D003094:Collagen / Q000737:chemistry / Q000494:pharmacology; D018014:Gene Transfer Techniques; D006801:Humans; D020100:Hydrogels / Q000737:chemistry / Q000494:pharmacology*; D038982:Integrin alpha2beta1 / Q000737:chemistry*; D008297:Male; D059630:Mesenchymal Stem Cells; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D023822:Tissue Engineering; D014945:Wound Healing / Q000187:drug effects
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D020100:Hydrogels; D038982:Integrin alpha2beta1; D010455:Peptides; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D003094:Collagen
keywords: BMP-2; Bone healing; Hydrogel; Integrin-specific; Polyethylene glycol; Protein delivery
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