title: Effect of rhBMP-2 dose on bone formation/maturation in a rat critical-size calvarial defect model.
abstract: BACKGROUND
  Application of recombinant human bone morphogenetic protein-2 (rhBMP-2) has been associated with significant adverse events in craniofacial settings, including swelling and seroma formation. Recent work has demonstrated an inverse relationship between bone formation/maturation and rhBMP-2 dose, frequency/severity of adverse events increasing with rising dose.
  
  
  OBJECTIVE
  The objective of this study was to determine the most effective dose for rhBMP-2 soak-loaded onto an absorbable collagen sponge (ACS) carrier for bone formation/maturation using an established defect model.
  
  
  METHODS
  One hundred sixty-eight outbred male Sprague-Dawley rats, age 11-13 weeks, weight 325-375 g randomized into seven groups of 24 subdivided into groups of eight, were used to provide radiographic and light microscopy observations of bone formation/maturation and aberrant healing events at 2, 4 and 8 weeks following application of rhBMP-2/ACS into critical-size, ø8-mm, through-through, calvarial osteotomy defects for a dose of 1.25, 2.5, 5.0, 10.0 and 20.0 μg rhBMP-2/defect, or serve as ACS or sham-surgery controls.
  
  
  RESULTS
  rhBMP-2 dosages ≥ 2.5 μg/defect showed histological defect closure >90% within 2 weeks, and complete resolution within 4 weeks. Adverse healing events including swelling, excessive bone formation or seroma formation could not be determined with certainty in this defect model. Notably ACS control sites showed complete defect closure at the 8-week healing interval.
  
  
  CONCLUSIONS
  rhBMP-2/ACS accelerates local bone formation in the rat critical-size through-through calvarial defect model once reaching an osteoinductive dose threshold. This threshold may already be reached at a 1.25-/2.5-μg dose in this model. No further enhancement to bone formation/maturation may be observed adding rhBMP-2 above the 2.5-μg dose. The 1.25-20.0 μg dose range did not invoke appreciable aberrant healing events.
authors.affiliation: Laboratory for Applied Periodontal & Craniofacial Regeneration (LAPCR), Georgia Regents University College of Dental Medicine, Augusta, GA, USA; US Army Dental Activity, Fort Bragg, NC, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Pelaez
authors.forename: Cristiano
authors.initials: C
authors.lastname: Susin
authors.forename: Jaebum
authors.initials: J
authors.lastname: Lee
authors.forename: Tiago
authors.initials: T
authors.lastname: Fiorini
authors.forename: Frederick C
authors.initials: FC
authors.lastname: Bisch
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Dixon
authors.forename: James C
authors.initials: JC
authors.lastname: McPherson
authors.forename: Amanda N
authors.initials: AN
authors.lastname: Buxton
authors.forename: Ulf M E
authors.initials: UM
authors.lastname: Wikesjö
mesh_terms: D020341:Absorbable Implants; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001847:Bone Diseases / Q000188:drug therapy*; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage / Q000627:therapeutic use*; D002113:Calcification, Physiologic / Q000187:drug effects; D003094:Collagen; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D008297:Male; D010012:Osteogenesis / Q000187:drug effects*; D010294:Parietal Bone / Q000187:drug effects* / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000627:therapeutic use*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D055396:Bone Morphogenetic Protein 2; D004337:Drug Carriers; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D003094:Collagen
keywords: BMP-2; animal models; bone formation; bone maturation; calvarial bone; dose