title: Guided bone regeneration using resorbable membrane and different bone substitutes: Early histological and molecular events.
abstract: Bone insufficiency remains a major challenge for bone-anchored implants. The combination of guided bone regeneration (GBR) and bone augmentation is an established procedure to restore the bone. However, a proper understanding of the interactions between the bone substitute and GBR membrane materials and the bone-healing environment is lacking. This study aimed to investigate the early events of bone healing and the cellular activities in response to a combination of GBR membrane and different calcium phosphate (CaP) materials. Defects were created in the trabecular region of rat femurs, and filled with deproteinized bovine bone (DBB), hydroxyapatite (HA) or strontium-doped HA (SrHA) or left empty (sham). All the defects were covered with an extracellular matrix membrane. Defects were harvested after 12h, 3d and 6d for histology/histomorphometry, immunohistochemistry and gene expression analyses. Histology revealed new bone, at 6d, in all the defects. Larger amount of bone was observed in the SrHA-filled defect. This was in parallel with the reduced expression of osteoclastic genes (CR and CatK) and the osteoblast-osteoclast coupling gene (RANKL) in the SrHA defects. Immunohistochemistry indicated fewer osteoclasts in the SrHA defects. The observations of CD68 and periostin-expressing cells in the membrane per se indicated that the membrane may contribute to the healing process in the defect. It is concluded that the bone-promoting effects of Sr in vivo are mediated by a reduction in catabolic and osteoblast-osteoclast coupling processes. The combination of a bioactive membrane and CaP bone substitute material doped with Sr may produce early synergistic effects during GBR.
  
  
  CONCLUSIONS
  The study provides novel molecular, cellular and structural evidence on the promotion of early bone regeneration in response to synthetic strontium-containing hydroxyapatite (SrHA) substitute, in combination with a resorbable, guided bone regeneration (GBR) membrane. The prevailing view, based mainly upon in vitro data, is that the beneficial effects of Sr are exerted by the stimulation of bone-forming cells (osteoblasts) and the inhibition of bone-resorbing cells (osteoclasts). In contrast, the present study demonstrates that the local effect of Sr in vivo is predominantly via the inhibition of osteoclast number and activity and the reduction of osteoblast-osteoclast coupling. This experimental data will form the basis for clinical studies, using this material as an interesting bone substitute for guided bone regeneration.
authors.affiliation: BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden; Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Box 412, SE-405 30 Gothenburg, Sweden.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Elgali
authors.affiliation: BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden; Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Box 412, SE-405 30 Gothenburg, Sweden; The Brånemark Clinic, Institute of Odontology, Public Dental Health Care, Gothenburg, Sweden.
authors.forename: Alberto
authors.initials: A
authors.lastname: Turri
authors.affiliation: Applied Material Sciences, Department of Engineering Sciences, Uppsala University, Box 534, 751 21 Uppsala, Sweden.
authors.forename: Wei
authors.initials: W
authors.lastname: Xia
authors.affiliation: BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden; Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Box 412, SE-405 30 Gothenburg, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Norlindh
authors.affiliation: BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden; Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Box 412, SE-405 30 Gothenburg, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Johansson
authors.affiliation: BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden; Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Box 412, SE-405 30 Gothenburg, Sweden; Department of Oral, Maxillofacial Surgery and Research and Development, NU-Hospital Organization, Trollhättan, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Dahlin
authors.affiliation: BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden; Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Box 412, SE-405 30 Gothenburg, Sweden. Electronic address: peter.thomsen@biomaterials.gu.se.
authors.forename: Peter
authors.initials: P
authors.lastname: Thomsen
authors.affiliation: BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden; Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Box 412, SE-405 30 Gothenburg, Sweden.
authors.forename: Omar
authors.initials: O
authors.lastname: Omar
mesh_terms: D020341:Absorbable Implants; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism*; D001861:Bone Regeneration; D018786:Bone Substitutes / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D048091:Guided Tissue Regeneration / Q000379:methods*; D008297:Male; D008567:Membranes, Artificial; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000943:Antigens, Differentiation; D018786:Bone Substitutes; D008567:Membranes, Artificial
keywords: Bone substitute; Gene expression; Guided bone regeneration; Membrane; Strontium