title: Quantitative assessment of scaffold and growth factor-mediated repair of critically sized bone defects.
abstract: An 8-mm rat segmental defect model was used to evaluate quantitatively the ability of longitudinally oriented poly(L-lactide-co-D,L-lactide) scaffolds with or without growth factors to promote bone healing. BMP-2 and TGF-beta3, combined with RGD-alginate hydrogel, were co-delivered to femoral defects within the polymer scaffolds at a dose previously shown to synergistically induce ectopic mineralization. A novel modular composite implant design was used to achieve reproducible stable fixation, provide a window for longitudinal in vivo micro-CT monitoring of 3D bone ingrowth, and allow torsional biomechanical testing of functional integration. Sequential micro-CT analysis showed that bone ingrowth increased significantly between 4 and 16 weeks for the scaffold-treated defects with or without growth factors, but no increase with time was observed in empty defect controls. Treatment with scaffold alone improved defect stability at 16 weeks compared to nontreatment, but did not achieve bone union or restoration of mechanical function. Augmentation of scaffolds with BMP-2 and TGF-beta3 significantly increased bone formation at both 4 and 16 weeks compared to nontreatment, but only produced bone bridging of the defect region in two of six cases. Histological evaluation indicated that bone formed first at the periphery of the scaffolds, followed by more limited mineral deposition within the scaffold interior, suggesting that the cells participating in the initial healing response were primarily derived from periosteum. This study introduces a challenging segmental defect model that facilitates quantitative evaluation of strategies to repair critically sized bone defects. Healing of the defect region was improved by implanting structural polymeric scaffolds infused with growth factors incorporated within RGD-alginate. However, functional integration of the constructs appeared limited by continued presence of slow-degrading scaffolds and suboptimal dose or delivery of osteoinductive signals.
authors.affiliation: Orthopaedic Research Laboratory, Woodruff School of Mechanical Engineering, Georgia Institute of Technology, IBB Room 2311, 315 Ferst Drive NW, Atlanta, Georgia 30332, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Oest
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Dupont
authors.forename: Hyun-Joon
authors.initials: HJ
authors.lastname: Kong
authors.forename: David J
authors.initials: DJ
authors.lastname: Mooney
authors.forename: Robert E
authors.initials: RE
authors.lastname: Guldberg
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000737:chemistry / Q000494:pharmacology*; D001861:Bone Regeneration / Q000187:drug effects* / Q000502:physiology; D019245:Compressive Strength; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000293:injuries; D019344:Lactic Acid / Q000737:chemistry / Q000494:pharmacology*; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D010027:Osteotomy; D011100:Polyglycolic Acid / Q000737:chemistry / Q000494:pharmacology*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D023822:Tissue Engineering; D014057:Tomography, X-Ray Computed; D016212:Transforming Growth Factor beta / Q000737:chemistry / Q000494:pharmacology*; D053782:Transforming Growth Factor beta3 / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001672:Biocompatible Materials; C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D011108:Polymers; D016212:Transforming Growth Factor beta; D053782:Transforming Growth Factor beta3; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid