title: Engineering a humanized bone organ model in mice to study bone metastases.
abstract: Current in vivo models for investigating human primary bone tumors and cancer metastasis to the bone rely on the injection of human cancer cells into the mouse skeleton. This approach does not mimic species-specific mechanisms occurring in human diseases and may preclude successful clinical translation. We have developed a protocol to engineer humanized bone within immunodeficient hosts, which can be adapted to study the interactions between human cancer cells and a humanized bone microenvironment in vivo. A researcher trained in the principles of tissue engineering will be able to execute the protocol and yield study results within 4-6 months. Additive biomanufactured scaffolds seeded and cultured with human bone-forming cells are implanted ectopically in combination with osteogenic factors into mice to generate a physiological bone 'organ', which is partially humanized. The model comprises human bone cells and secreted extracellular matrix (ECM); however, other components of the engineered tissue, such as the vasculature, are of murine origin. The model can be further humanized through the engraftment of human hematopoietic stem cells (HSCs) that can lead to human hematopoiesis within the murine host. The humanized organ bone model has been well characterized and validated and allows dissection of some of the mechanisms of the bone metastatic processes in prostate and breast cancer.
authors.affiliation: Queensland University of Technology (QUT), Brisbane, Queensland, Australia.
authors.forename: Laure C
authors.identifier: 0000-0003-1427-9762
authors.initials: LC
authors.lastname: Martine
authors.affiliation: Queensland University of Technology (QUT), Brisbane, Queensland, Australia.|Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Boris M
authors.initials: BM
authors.lastname: Holzapfel
authors.affiliation: Queensland University of Technology (QUT), Brisbane, Queensland, Australia.
authors.forename: Jacqui A
authors.initials: JA
authors.lastname: McGovern
authors.affiliation: Queensland University of Technology (QUT), Brisbane, Queensland, Australia.|Department of Orthopedics for the University of Regensburg, Asklepios Klinikum Bad Abbach, Bad Abbach, Germany.|Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Wagner
authors.affiliation: Queensland University of Technology (QUT), Brisbane, Queensland, Australia.|Department of Obstetrics and Gynecology, Martin-Luther-Krankenhaus, Academic Teaching Hospital of the Charité Berlin, Berlin, Germany.
authors.forename: Verena M
authors.initials: VM
authors.lastname: Quent
authors.affiliation: Queensland University of Technology (QUT), Brisbane, Queensland, Australia.
authors.forename: Parisa
authors.initials: P
authors.lastname: Hesami
authors.affiliation: Queensland University of Technology (QUT), Brisbane, Queensland, Australia.
authors.forename: Felix M
authors.initials: FM
authors.lastname: Wunner
authors.affiliation: Queensland University of Technology (QUT), Brisbane, Queensland, Australia.
authors.forename: Cedryck
authors.initials: C
authors.lastname: Vaquette
authors.affiliation: Queensland University of Technology (QUT), Brisbane, Queensland, Australia.
authors.forename: Elena M
authors.identifier: 0000-0001-9005-7497
authors.initials: EM
authors.lastname: De-Juan-Pardo
authors.affiliation: Queensland University of Technology (QUT), Brisbane, Queensland, Australia.
authors.forename: Toby D
authors.initials: TD
authors.lastname: Brown
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Bianca
authors.initials: B
authors.lastname: Nowlan
authors.affiliation: Queensland University of Technology (QUT), Brisbane, Queensland, Australia.|Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.
authors.forename: Dan Jing
authors.initials: DJ
authors.lastname: Wu
authors.affiliation: Queensland University of Technology (QUT), Brisbane, Queensland, Australia.
authors.forename: Cosmo Orlando
authors.initials: CO
authors.lastname: Hutmacher
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Davide
authors.initials: D
authors.lastname: Moi
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Oussenko
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Elia
authors.initials: E
authors.lastname: Piccinini
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Zandstra
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Roberta
authors.initials: R
authors.lastname: Mazzieri
authors.affiliation: Stem Cell Biology Group - Blood and Bone Diseases Program, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.|Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Lévesque
authors.affiliation: Queensland University of Technology (QUT), Brisbane, Queensland, Australia.|Department of Functional Materials in Medicine and Dentistry, and Bavarian Polymer Institute, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Dalton
authors.affiliation: Queensland University of Technology (QUT), Brisbane, Queensland, Australia.|Biotec TU Dresden, Dresden, Germany.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Taubenberger
authors.affiliation: Queensland University of Technology (QUT), Brisbane, Queensland, Australia.|George W Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA.|Institute for Advanced Study, Technical University Munich, Garching, Germany.
authors.forename: Dietmar W
authors.identifier: 0000-0001-5678-2134
authors.initials: DW
authors.lastname: Hutmacher
mesh_terms: D000230:Adenocarcinoma; D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000494:pharmacology; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary*; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology*; D001943:Breast Neoplasms / Q000473:pathology; D004195:Disease Models, Animal; D004560:Electricity; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000473:pathology; D023822:Tissue Engineering / Q000295:instrumentation / Q000379:methods*
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7