title: A novel nonviral gene delivery tool of BMP-2 for the reconstitution of critical-size bone defects in rats.
abstract: The osseointegration of bone implants, implant failure, and the bridging of critical-size bone defects are frequent clinical challenges. Deficiencies in endogenous bone healing can be resolved through the local administration of suitable recombinant growth factors (GFs). In preclinical models, gene-therapy-supported bone healing has proven promising for overcoming certain limitations of GFs. We report the dose-dependent bridging of critical-size mandibular bone defects (CSDs) in a rat model using a non-viral BMP-2-encoding copolymer-protected gene vector (pBMP-2) embedded in poly(d, l-lactide) (PDLLA) coatings on titanium discs that were used to cover drill holes in the mandibles of 53 male Sprague Dawley rats. After sacrificing, the mandibles were subjected to micro-computed tomography (µCT), micro-radiography, histology, and fluorescence analyses to evaluate bone regeneration. pBMP-2 in PDLLA-coated titanium implants promoted partial bridging of bone defects within 14 days and complete defect healing within 112 days when the DNA dose per implant did not exceed 2.5 µg. No bridging was observed in untreated control CSDs. Thus, the delivery of plasmid DNA coding for BMP-2 appears to be a potent method for controlled new-bone formation with an inverse dose dependency. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2441-2455, 2016.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany.|Institute of Molecular Immunology and Experimental Oncology, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kolk
authors.affiliation: Department of Orthopeadic Sports Medicine, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tischer
authors.affiliation: Institute of Molecular Immunology and Experimental Oncology, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Koch
authors.affiliation: Department of Orthopeadic Sports Medicine, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Vogt
authors.affiliation: Institute of Medical Statistics and Epidemiology, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Haller
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Smeets
authors.affiliation: Department of Oral and Maxillofacial Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany.
authors.forename: Kilian
authors.initials: K
authors.lastname: Kreutzer
authors.affiliation: Institute of Molecular Immunology and Experimental Oncology, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Plank
authors.affiliation: Department of Oral and Maxillofacial Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bissinger
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics*; D001861:Bone Regeneration; D018786:Bone Substitutes / Q000737:chemistry*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D008297:Male; D008334:Mandible / Q000473:pathology / Q000502:physiology; D008338:Mandibular Injuries / Q000473:pathology / Q000628:therapy*; D016348:Osseointegration; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D011091:Polyesters / Q000737:chemistry; D019736:Prostheses and Implants; D017207:Rats, Sprague-Dawley; D013499:Surface Properties; D014025:Titanium / Q000737:chemistry
chemical_list: D055396:Bone Morphogenetic Protein 2; D018786:Bone Substitutes; D011091:Polyesters; C033616:poly(lactide); D014025:Titanium
keywords: bone morphogenetic protein 2-plasmid; de novo bone-formation; gene-activated matrix; nonviral gene transfer; protective copolymer; titanium surface