title: Osteointegration of hydroxyapatite-titanium implants coated with nonglycosylated recombinant human bone morphogenetic protein-2 (BMP-2) in aged sheep.
abstract: Osteointegration of metal implants into aged organisms can be severely compromised due to reduced healing capacity of bone, lack of precursor cells for new bone formation, or osteoporosis. Here, we report on successful implant healing in a novel model of aged sheep in the presence of nonglycosylated bone morphogenetic protein 2 (BMP-2). Ewes of 8 to 12 years with significant radiologic and histologic signs of osteoporosis and adipocytic bone marrow received a cylindrical hydroxyapatite-titanium implant of 12 x 10 mm. BMP-2 has been produced as a bacterial recombinant fusion protein with maltose-binding protein and in vitro generation of mature BMP-2 by renaturation and proteolytic cleavage. A BMP-2 inhibition ELISA was developed to measure the in vitro release kinetics of bioactive human BMP-2 from immersed solid implant materials by using Escherichia coli expressed and biotinylated recombinant human BMP-2 receptor IA extracellular domain (ALK-3 ECD). The implants were placed laterally below both tibial plateaus, with the left leg implant carrying 380 microg BMP-2. Both implant types became integrated within the following 20 weeks. The control implant only integrated at the cortical bone, and little new bone formation was found within the pre-existing trabecular bone or the marrow cavity. Marrow fat tissue was partially replaced by unspecific connective tissue. In contrast, BMP-2-coated implants initiated significant new bone formation, initially in trabecular arrangements to be replaced by cortical-like bone after 20 weeks. The new bone was oriented towards the cylinder. Highly viable bone marrow appeared and filled the lacunar structures of the new bone. In mechanical tests, the BMP-2-coated implants displayed in average 50% higher stability. This animal model provided first evidence that application of nonglycosylated BMP-2 coated on solid implants may foster bone healing and regeneration even in aged-compromised individuals.
authors.affiliation: Department of Orthopaedics of the University of Jena at the Waldkrankenhaus Rudolf Elle, Jena, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Sachse
authors.forename: A
authors.initials: A
authors.lastname: Wagner
authors.forename: M
authors.initials: M
authors.lastname: Keller
authors.forename: O
authors.initials: O
authors.lastname: Wagner
authors.forename: W-D
authors.initials: WD
authors.lastname: Wetzel
authors.forename: F
authors.initials: F
authors.lastname: Layher
authors.forename: R-A
authors.initials: RA
authors.lastname: Venbrocks
authors.forename: P
authors.initials: P
authors.lastname: Hortschansky
authors.forename: M
authors.initials: M
authors.lastname: Pietraszczyk
authors.forename: B
authors.initials: B
authors.lastname: Wiederanders
authors.forename: H J
authors.initials: HJ
authors.lastname: Hempel
authors.forename: J
authors.initials: J
authors.lastname: Bossert
authors.forename: J
authors.initials: J
authors.lastname: Horn
authors.forename: K
authors.initials: K
authors.lastname: Schmuck
authors.forename: J
authors.initials: J
authors.lastname: Mollenhauer
mesh_terms: D000375:Aging; D000818:Animals; D001696:Biomechanical Phenomena; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D001861:Bone Regeneration; D016723:Bone Remodeling; D004195:Disease Models, Animal; D005260:Female; D006031:Glycosylation; D006882:Hydroxyapatites; D008954:Models, Biological; D016348:Osseointegration; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology*; D010024:Osteoporosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019736:Prostheses and Implants; D011993:Recombinant Fusion Proteins; D012756:Sheep; D013977:Tibia / Q000502:physiology; D014025:Titanium; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D006882:Hydroxyapatites; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; C098170:hydroxyapatite-titanium alloy; D014025:Titanium