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Orthotopic Bone Formation by Streamlined Engineering and Devitalization of Human Hypertrophic Cartilage

Pigeot, Sébastien ; Bourgine, Paul Emile LU orcid ; Claude, Jaquiery ; Scotti, Celeste ; Papadimitropoulos, Adam ; Todorov, Atanas ; Epple, Christian ; Peretti, Giuseppe M and Martin, Ivan (2020) In International Journal of Molecular Sciences 21(19).
Abstract

Most bones of the human body form and heal through endochondral ossification, whereby hypertrophic cartilage (HyC) is formed and subsequently remodeled into bone. We previously demonstrated that HyC can be engineered from human mesenchymal stromal cells (hMSC), and subsequently devitalized by apoptosis induction. The resulting extracellular matrix (ECM) tissue retained osteoinductive properties, leading to ectopic bone formation. In this study, we aimed at engineering and devitalizing upscaled quantities of HyC ECM within a perfusion bioreactor, followed by in vivo assessment in an orthotopic bone repair model. We hypothesized that the devitalized HyC ECM would outperform a clinical product currently used for bone reconstructive... (More)

Most bones of the human body form and heal through endochondral ossification, whereby hypertrophic cartilage (HyC) is formed and subsequently remodeled into bone. We previously demonstrated that HyC can be engineered from human mesenchymal stromal cells (hMSC), and subsequently devitalized by apoptosis induction. The resulting extracellular matrix (ECM) tissue retained osteoinductive properties, leading to ectopic bone formation. In this study, we aimed at engineering and devitalizing upscaled quantities of HyC ECM within a perfusion bioreactor, followed by in vivo assessment in an orthotopic bone repair model. We hypothesized that the devitalized HyC ECM would outperform a clinical product currently used for bone reconstructive surgery. Human MSC were genetically engineered with a gene cassette enabling apoptosis induction upon addition of an adjuvant. Engineered hMSC were seeded, differentiated, and devitalized within a perfusion bioreactor. The resulting HyC ECM was subsequently implanted in a 10-mm rabbit calvarial defect model, with processed human bone (Maxgraft®) as control. Human MSC cultured in the perfusion bioreactor generated a homogenous HyC ECM and were efficiently induced towards apoptosis. Following six weeks of in vivo implantation, microcomputed tomography and histological analyses of the defects revealed an increased bone formation in the defects filled with HyC ECM as compared to Maxgraft®. This work demonstrates the suitability of engineered devitalized HyC ECM as a bone substitute material, with a performance superior to a state-of-the-art commercial graft. Streamlined generation of the devitalized tissue transplant within a perfusion bioreactor is relevant towards standardized and automated manufacturing of a clinical product.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
Animals, Apoptosis/genetics, Bone Remodeling/genetics, Bone Substitutes/therapeutic use, Cartilage/growth & development, Cell Differentiation/genetics, Extracellular Matrix/genetics, Humans, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells/cytology, Osteogenesis/genetics, Rabbits, Skull/growth & development, Tissue Engineering/methods, Tissue Scaffolds, Wound Healing/genetics
in
International Journal of Molecular Sciences
volume
21
issue
19
article number
7233
publisher
MDPI AG
external identifiers
  • pmid:33008121
  • scopus:85091964415
ISSN
1422-0067
DOI
10.3390/ijms21197233
language
English
LU publication?
yes
id
6b8034c4-6268-447d-bd2a-f6e5e313ae29
date added to LUP
2022-02-10 09:20:39
date last changed
2024-03-07 22:46:31
@article{6b8034c4-6268-447d-bd2a-f6e5e313ae29,
  abstract     = {{<p>Most bones of the human body form and heal through endochondral ossification, whereby hypertrophic cartilage (HyC) is formed and subsequently remodeled into bone. We previously demonstrated that HyC can be engineered from human mesenchymal stromal cells (hMSC), and subsequently devitalized by apoptosis induction. The resulting extracellular matrix (ECM) tissue retained osteoinductive properties, leading to ectopic bone formation. In this study, we aimed at engineering and devitalizing upscaled quantities of HyC ECM within a perfusion bioreactor, followed by in vivo assessment in an orthotopic bone repair model. We hypothesized that the devitalized HyC ECM would outperform a clinical product currently used for bone reconstructive surgery. Human MSC were genetically engineered with a gene cassette enabling apoptosis induction upon addition of an adjuvant. Engineered hMSC were seeded, differentiated, and devitalized within a perfusion bioreactor. The resulting HyC ECM was subsequently implanted in a 10-mm rabbit calvarial defect model, with processed human bone (Maxgraft®) as control. Human MSC cultured in the perfusion bioreactor generated a homogenous HyC ECM and were efficiently induced towards apoptosis. Following six weeks of in vivo implantation, microcomputed tomography and histological analyses of the defects revealed an increased bone formation in the defects filled with HyC ECM as compared to Maxgraft®. This work demonstrates the suitability of engineered devitalized HyC ECM as a bone substitute material, with a performance superior to a state-of-the-art commercial graft. Streamlined generation of the devitalized tissue transplant within a perfusion bioreactor is relevant towards standardized and automated manufacturing of a clinical product.</p>}},
  author       = {{Pigeot, Sébastien and Bourgine, Paul Emile and Claude, Jaquiery and Scotti, Celeste and Papadimitropoulos, Adam and Todorov, Atanas and Epple, Christian and Peretti, Giuseppe M and Martin, Ivan}},
  issn         = {{1422-0067}},
  keywords     = {{Animals; Apoptosis/genetics; Bone Remodeling/genetics; Bone Substitutes/therapeutic use; Cartilage/growth & development; Cell Differentiation/genetics; Extracellular Matrix/genetics; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells/cytology; Osteogenesis/genetics; Rabbits; Skull/growth & development; Tissue Engineering/methods; Tissue Scaffolds; Wound Healing/genetics}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{19}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{Orthotopic Bone Formation by Streamlined Engineering and Devitalization of Human Hypertrophic Cartilage}},
  url          = {{http://dx.doi.org/10.3390/ijms21197233}},
  doi          = {{10.3390/ijms21197233}},
  volume       = {{21}},
  year         = {{2020}},
}