title: A Validated Preclinical Animal Model for Primary Bone Tumor Research.
abstract: BACKGROUND
  Despite the introduction of 21st-century surgical and neoadjuvant treatment modalities, survival of patients with osteosarcoma (OS) has not improved in two decades. Advances will depend in part on the development of clinically relevant and reliable animal models. This report describes the engineering and validation of a humanized tissue-engineered bone organ (hTEBO) for preclinical research on primary bone tumors in order to minimize false-positive and false-negative results due to interspecies differences in current xenograft models.
  
  
  METHODS
  Pelvic bone and marrow fragments were harvested from patients during reaming of the acetabulum during hip arthroplasty. HTEBOs were engineered by embedding fragments in a fibrin matrix containing bone morphogenetic protein-7 (BMP-7) and implanted into NOD-scid mice. After 10 weeks of subcutaneous growth, one group of hTEBOs was harvested to analyze the degree of humanization. A second group was injected with human luciferase-labeled OS (Luc-SAOS-2) cells. Tumor growth was followed in vivo with bioluminescence imaging. After 5 weeks, the OS tumors were harvested and analyzed. They were also compared with tumors created via intratibial injection.
  
  
  RESULTS
  After 10 weeks of in vivo growth, a new bone organ containing human bone matrix as well as viable and functional human hematopoietic cells developed. Five weeks after injection of Luc-SAOS-2 cells into this humanized bone microenvironment, spontaneous metastatic spread to the lung was evident. Relevant prognostic markers such as vascular endothelial growth factor (VEGF) and periostin were found to be positive in OS tumors grown within the humanized microenvironment but not in tumors created in murine tibial bones. Hypoxia-inducible transcription factor-2α (HIF-2α) was detected only in the humanized OS.
  
  
  CONCLUSIONS
  We report an in vivo model that contains human bone matrix and marrow components in one organ. BMP-7 made it possible to maintain viable mesenchymal and hematopoietic stem cells and created a bone microenvironment mimicking human physiology.
  
  
  CONCLUSIONS
  This novel platform enables preclinical research on primary bone tumors in order to test new treatment options.
authors.affiliation: Regenerative Medicine, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia Department of Orthopedics, Asklepios Klinikum Bad Abbach, University of Regensburg, Bad Abbach, Germany Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Wagner
authors.affiliation: Regenerative Medicine, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia Orthopedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany.
authors.forename: Boris M
authors.initials: BM
authors.lastname: Holzapfel
authors.affiliation: Regenerative Medicine, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
authors.forename: Laure
authors.initials: L
authors.lastname: Thibaudeau
authors.affiliation: Institute of Pathology, University Clinic Rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Straub
authors.affiliation: Australian Prostate Cancer Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, at Translational Research Institute, Woolloongabba, Australia.
authors.forename: Ming-Tat
authors.initials: MT
authors.lastname: Ling
authors.affiliation: Department of Orthopedics, Asklepios Klinikum Bad Abbach, University of Regensburg, Bad Abbach, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Grifka
authors.affiliation: Regenerative Medicine, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
authors.forename: Daniela
authors.initials: D
authors.lastname: Loessner
authors.affiliation: Stem Cell Biology Group-Blood and Bone Diseases Program, Mater Research Institute, Translational Research Institute, Woolloongabba, Australia The University of Queensland, Herston, Australia.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Lévesque
authors.affiliation: Regenerative Medicine, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia Institute for Advanced Study, Technical University Munich, Munich, Germany dietmar.hutmacher@qut.edu.au.
authors.forename: Dietmar W
authors.initials: DW
authors.lastname: Hutmacher
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism*; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D055419:Bone Morphogenetic Protein 7; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A