Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle
Large segmental defects in bone fail to heal and remain a clinical problem. Muscle is highly osteogenic, and preliminary data suggest that autologous muscle tissue expressing bone morphogenetic protein-2 (BMP-2) efficiently heals critical size defects in rats. Translation into possible human clinica...
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AO Research Institute Davos
2015-09-01
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doaj-3ef358fe86804d52828a878a4dea2ba22020-11-24T22:13:39Zeng AO Research Institute DavosEuropean Cells & Materials1473-22622015-09-013011813110.22203/eCM.v030a09Rapid and reliable healing of critical size bone defects with genetically modified sheep muscleF LiuE FerreiraRM PorterV GlattM SchinhanZ ShenMA RandolphCA Kirker-HeadC WehlingMS VrahasCH Evans0JW WellsRehabilitation Medicine Research Center, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USALarge segmental defects in bone fail to heal and remain a clinical problem. Muscle is highly osteogenic, and preliminary data suggest that autologous muscle tissue expressing bone morphogenetic protein-2 (BMP-2) efficiently heals critical size defects in rats. Translation into possible human clinical trials requires, inter alia, demonstration of efficacy in a large animal, such as the sheep. Scale-up is fraught with numerous biological, anatomical, mechanical and structural variables, which cannot be addressed systematically because of cost and other practical issues. For this reason, we developed a translational model enabling us to isolate the biological question of whether sheep muscle, transduced with adenovirus expressing BMP-2, could heal critical size defects in vivo. Initial experiments in athymic rats noted strong healing in only about one-third of animals because of unexpected immune responses to sheep antigens. For this reason, subsequent experiments were performed with Fischer rats under transient immunosuppression. Such experiments confirmed remarkably rapid and reliable healing of the defects in all rats, with bridging by 2 weeks and remodelling as early as 3-4 weeks, despite BMP-2 production only in nanogram quantities and persisting for only 1-3 weeks. By 8 weeks the healed defects contained well-organised new bone with advanced neo-cortication and abundant marrow. Bone mineral content and mechanical strength were close to normal values. These data demonstrate the utility of this model when adapting this technology for bone healing in sheep, as a prelude to human clinical trials.http://www.ecmjournal.org/papers/vol030/pdf/v030a09.pdfBone healinggene therapymuscleadenovirusbone morphogenetic proteinsheepratimmunosuppression |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
F Liu E Ferreira RM Porter V Glatt M Schinhan Z Shen MA Randolph CA Kirker-Head C Wehling MS Vrahas CH Evans JW Wells |
spellingShingle |
F Liu E Ferreira RM Porter V Glatt M Schinhan Z Shen MA Randolph CA Kirker-Head C Wehling MS Vrahas CH Evans JW Wells Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle European Cells & Materials Bone healing gene therapy muscle adenovirus bone morphogenetic protein sheep rat immunosuppression |
author_facet |
F Liu E Ferreira RM Porter V Glatt M Schinhan Z Shen MA Randolph CA Kirker-Head C Wehling MS Vrahas CH Evans JW Wells |
author_sort |
F Liu |
title |
Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle |
title_short |
Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle |
title_full |
Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle |
title_fullStr |
Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle |
title_full_unstemmed |
Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle |
title_sort |
rapid and reliable healing of critical size bone defects with genetically modified sheep muscle |
publisher |
AO Research Institute Davos |
series |
European Cells & Materials |
issn |
1473-2262 |
publishDate |
2015-09-01 |
description |
Large segmental defects in bone fail to heal and remain a clinical problem. Muscle is highly osteogenic, and preliminary data suggest that autologous muscle tissue expressing bone morphogenetic protein-2 (BMP-2) efficiently heals critical size defects in rats. Translation into possible human clinical trials requires, inter alia, demonstration of efficacy in a large animal, such as the sheep. Scale-up is fraught with numerous biological, anatomical, mechanical and structural variables, which cannot be addressed systematically because of cost and other practical issues. For this reason, we developed a translational model enabling us to isolate the biological question of whether sheep muscle, transduced with adenovirus expressing BMP-2, could heal critical size defects in vivo. Initial experiments in athymic rats noted strong healing in only about one-third of animals because of unexpected immune responses to sheep antigens. For this reason, subsequent experiments were performed with Fischer rats under transient immunosuppression. Such experiments confirmed remarkably rapid and reliable healing of the defects in all rats, with bridging by 2 weeks and remodelling as early as 3-4 weeks, despite BMP-2 production only in nanogram quantities and persisting for only 1-3 weeks. By 8 weeks the healed defects contained well-organised new bone with advanced neo-cortication and abundant marrow. Bone mineral content and mechanical strength were close to normal values. These data demonstrate the utility of this model when adapting this technology for bone healing in sheep, as a prelude to human clinical trials. |
topic |
Bone healing gene therapy muscle adenovirus bone morphogenetic protein sheep rat immunosuppression |
url |
http://www.ecmjournal.org/papers/vol030/pdf/v030a09.pdf |
work_keys_str_mv |
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