Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle

F. Liu, E. Ferreira, R. M. Porter, V. Glatt, M. Schinhan, Z. Shen, M. A. Randolph, C. A. Kirker-Head, C. Wehling, M. S. Vrahas, Christopher H Evans, J. W. Wells

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)118-131
Number of pages14
JournalEuropean Cells and Materials
Volume30
StatePublished - 2015
Externally publishedYes

Fingerprint

Bone Morphogenetic Protein 2
Muscle
Sheep
Bone
Rats
Bone and Bones
Muscles
Defects
Clinical Trials
Nude Rats
Animals
Proteins
Inbred F344 Rats
Adenoviridae
Bone Density
Immunosuppression
Experiments
Reference Values
Bone Marrow
Strength of materials

Keywords

  • Adenovirus
  • Bone healing
  • Bone morphogenetic protein
  • Gene therapy
  • Immunosuppression
  • Muscle
  • Rat
  • Sheep

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Bioengineering
  • Biomedical Engineering
  • Biomaterials

Cite this

Liu, F., Ferreira, E., Porter, R. M., Glatt, V., Schinhan, M., Shen, Z., ... Wells, J. W. (2015). Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle. European Cells and Materials, 30, 118-131.

Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle. / Liu, F.; Ferreira, E.; Porter, R. M.; Glatt, V.; Schinhan, M.; Shen, Z.; Randolph, M. A.; Kirker-Head, C. A.; Wehling, C.; Vrahas, M. S.; Evans, Christopher H; Wells, J. W.

In: European Cells and Materials, Vol. 30, 2015, p. 118-131.

Research output: Contribution to journalArticle

Liu, F, Ferreira, E, Porter, RM, Glatt, V, Schinhan, M, Shen, Z, Randolph, MA, Kirker-Head, CA, Wehling, C, Vrahas, MS, Evans, CH & Wells, JW 2015, 'Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle', European Cells and Materials, vol. 30, pp. 118-131.
Liu F, Ferreira E, Porter RM, Glatt V, Schinhan M, Shen Z et al. Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle. European Cells and Materials. 2015;30:118-131.
Liu, F. ; Ferreira, E. ; Porter, R. M. ; Glatt, V. ; Schinhan, M. ; Shen, Z. ; Randolph, M. A. ; Kirker-Head, C. A. ; Wehling, C. ; Vrahas, M. S. ; Evans, Christopher H ; Wells, J. W. / Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle. In: European Cells and Materials. 2015 ; Vol. 30. pp. 118-131.
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