title: The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing.
abstract: OBJECTIVE
  The purpose of this study was to revise the clinical use of commercial BMP2 (Infuse) and BMP7 (Osigraft) based bone devices and explore the mechanism of action and efficacy of low BMP6 doses in a novel whole blood biocompatible device OSTEOGROW.
  
  
  METHODS
  Complications from the clinical use of BMP2 and BMP7 have been systemically reviewed in light of their role in bone remodeling. BMP6 function has been assessed in Bmp6-/- mice by μCT and skeletal histology, and has also been examined in mesenchymal stem cells (MSC), hematopoietic stem cells (HSC) and osteoclasts. Safety and efficacy of OSTEOGROW have been assessed in rats and rabbits.
  
  
  RESULTS
  Clinical use issues of BMP2 and BMP7 have been ascribed to the limited understanding of their role in bone remodeling at the time of device development for clinical trials. BMP2 and BMP7 in bone devices significantly promote bone resorption leading to osteolysis at the endosteal surfaces, while in parallel stimulating exuberant bone formation in surrounding tissues. Unbound BMP2 and BMP7 in bone devices precipitate on the bovine collagen and cause inflammation and swelling. OSTEOGROW required small amounts of BMP6, applied in a biocompatible blood coagulum carrier, for stimulating differentiation of MSCs and accelerated healing of critical size bone defects in animals, without bone resorption and inflammation. BMP6 decreased the number of osteoclasts derived from HSC, while BMP2 and BMP7 increased their number.
  
  
  CONCLUSIONS
  Current issues and challenges with commercial bone devices may be resolved by using novel BMP6 biocompatible device OSTEOGROW, which will be clinically tested in metaphyseal bone fractures, compartments where BMP2 and BMP7 have not been effective.
authors.affiliation: Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, University of Zagreb School of Medicine, Salata 11, 10000, Zagreb, Croatia, vukicev@mef.hr.
authors.forename: Slobodan
authors.initials: S
authors.lastname: Vukicevic
authors.forename: Hermann
authors.initials: H
authors.lastname: Oppermann
authors.forename: Donatella
authors.initials: D
authors.lastname: Verbanac
authors.forename: Morana
authors.initials: M
authors.lastname: Jankolija
authors.forename: Irena
authors.initials: I
authors.lastname: Popek
authors.forename: Jasna
authors.initials: J
authors.lastname: Curak
authors.forename: Jelena
authors.initials: J
authors.lastname: Brkljacic
authors.forename: Martina
authors.initials: M
authors.lastname: Pauk
authors.forename: Igor
authors.initials: I
authors.lastname: Erjavec
authors.forename: Igor
authors.initials: I
authors.lastname: Francetic
authors.forename: Ivo
authors.initials: I
authors.lastname: Dumic-Cule
authors.forename: Mislav
authors.initials: M
authors.lastname: Jelic
authors.forename: Dragan
authors.initials: D
authors.lastname: Durdevic
authors.forename: Tomislav
authors.initials: T
authors.lastname: Vlahovic
authors.forename: Ruder
authors.initials: R
authors.lastname: Novak
authors.forename: Vera
authors.initials: V
authors.lastname: Kufner
authors.forename: Tatjana
authors.initials: T
authors.lastname: Bordukalo Niksic
authors.forename: Marija
authors.initials: M
authors.lastname: Kozlovic
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Banic Tomisic
authors.forename: Jadranka
authors.initials: J
authors.lastname: Bubic-Spoljar
authors.forename: Ivancica
authors.initials: I
authors.lastname: Bastalic
authors.forename: Smiljka
authors.initials: S
authors.lastname: Vikic-Topic
authors.forename: Mihaela
authors.initials: M
authors.lastname: Peric
authors.forename: Marko
authors.initials: M
authors.lastname: Pecina
authors.forename: Lovorka
authors.initials: L
authors.lastname: Grgurevic
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology / Q000627:therapeutic use; D055418:Bone Morphogenetic Protein 6 / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D055419:Bone Morphogenetic Protein 7 / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D050723:Fractures, Bone / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D051381:Rats; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
chemical_list: D001672:Biocompatible Materials; D055396:Bone Morphogenetic Protein 2; D055418:Bone Morphogenetic Protein 6; D055419:Bone Morphogenetic Protein 7