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Sustained delivery of a heterodimer bone morphogenetic protein-2/7 via a collagen hydroxyapatite scaffold accelerates and improves critical femoral defect healing

Liu, Yang LU ; Puthia, Manoj LU ; Sheehy, Eamon J ; Ambite, Ines LU orcid ; Petrlova, Jitka LU ; Prithviraj, Sujeethkumar ; Oxborg, Maria Wimer ; Sebastian, Sujeesh LU orcid ; Vater, Corina and Zwingenberger, Stefan , et al. (2023) In Acta Biomaterialia 162. p.164-181
Abstract

Despite the glimmer of hope provided by the discovery and commercialization of bone morphogenetic protein-2 (BMP-2) as a bone graft substitute, side effects related to the use of supraphysiological doses have hindered its clinical usage. In this study, we compared the osteoinductive potential of BMP-2 homodimer with a heterodimer of BMP-2/7, both delivered via a collagen-hydroxyapatite (CHA) scaffold delivery system, with the aim to reduce the overall therapeutic BMP doses and the associated side-effects. We first show that the incorporation of hydroxyapatite in collagen-based BMP delivery systems is pivotal for achieving efficient BMP sequestration and controlled release. Using an ectopic implantation model, we then showed that the... (More)

Despite the glimmer of hope provided by the discovery and commercialization of bone morphogenetic protein-2 (BMP-2) as a bone graft substitute, side effects related to the use of supraphysiological doses have hindered its clinical usage. In this study, we compared the osteoinductive potential of BMP-2 homodimer with a heterodimer of BMP-2/7, both delivered via a collagen-hydroxyapatite (CHA) scaffold delivery system, with the aim to reduce the overall therapeutic BMP doses and the associated side-effects. We first show that the incorporation of hydroxyapatite in collagen-based BMP delivery systems is pivotal for achieving efficient BMP sequestration and controlled release. Using an ectopic implantation model, we then showed that the CHA+BMP-2/7 was more osteoinductive than CHA+BMP-2. Further evaluation of the molecular mechanisms responsible for this increased osteoinductivity at an early stage in the regeneration process indicated that the CHA+BMP-2/7 enhanced progenitor cell homing at the implantation site, upregulated the key transcriptomic determinants of bone formation, and increased the production of bone extracellular matrix components. Using fluorescently labelled BMP-2/7 and BMP-2, we demonstrated that the CHA scaffold provided a long-term delivery of both molecules for at least 20 days. Finally, using a rat femoral defect model, we showed that an ultra-low dose (0.5 µg) of BMP-2/7 accelerated fracture healing and performed at a level comparable to 20-times higher BMP-2 dose. Our results indicate that the sustained delivery of BMP-2/7 via a CHA scaffold could bring us a step closer in the quest for the use of physiological growth factor doses in fracture healing. STATEMENT OF SIGNIFICANCE: • Incorporation of hydroxyapatite (HA) in a collagen scaffold dramatically improves bone morphogenic protein (BMP) sequestration via biophysical interactions with BMP, thereby providing more controlled BMP release compared with pristine collagen. • We then investigate the molecular mechanisms responsible for increased osteoinductive potential of a heterodimer BMP-2/7 with is clinically used counterpart, the BMP-2 homodimer. • The superior osteoinductive properties of BMP-2/7 are a consequence of its direct positive effect on progenitor cell homing at the implantation site, which consequently leads to upregulation of cartilage and bone related genes and biochemical markers. • An ultra-low dose of BMP-2/7 delivered via a collagen-HA (CHA) scaffold leads to accelerated healing of a critical femoral defect in rats while a 20-times higher BMP-2 dose was required to achieve comparable results.

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Contribution to journal
publication status
published
subject
keywords
Rats, Animals, Durapatite/pharmacology, Collagen/pharmacology, Osteogenesis, Bone and Bones, Fracture Healing, Bone Substitutes/pharmacology, Bone Morphogenetic Protein 2/pharmacology, Bone Regeneration
in
Acta Biomaterialia
volume
162
pages
164 - 181
publisher
Elsevier
external identifiers
  • scopus:85151531379
  • pmid:36967054
ISSN
1878-7568
DOI
10.1016/j.actbio.2023.03.028
language
English
LU publication?
yes
additional info
Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.
id
3543920c-9b40-452a-ab4c-1972a2bb3e77
date added to LUP
2023-05-17 12:47:35
date last changed
2024-06-29 04:10:03
@article{3543920c-9b40-452a-ab4c-1972a2bb3e77,
  abstract     = {{<p>Despite the glimmer of hope provided by the discovery and commercialization of bone morphogenetic protein-2 (BMP-2) as a bone graft substitute, side effects related to the use of supraphysiological doses have hindered its clinical usage. In this study, we compared the osteoinductive potential of BMP-2 homodimer with a heterodimer of BMP-2/7, both delivered via a collagen-hydroxyapatite (CHA) scaffold delivery system, with the aim to reduce the overall therapeutic BMP doses and the associated side-effects. We first show that the incorporation of hydroxyapatite in collagen-based BMP delivery systems is pivotal for achieving efficient BMP sequestration and controlled release. Using an ectopic implantation model, we then showed that the CHA+BMP-2/7 was more osteoinductive than CHA+BMP-2. Further evaluation of the molecular mechanisms responsible for this increased osteoinductivity at an early stage in the regeneration process indicated that the CHA+BMP-2/7 enhanced progenitor cell homing at the implantation site, upregulated the key transcriptomic determinants of bone formation, and increased the production of bone extracellular matrix components. Using fluorescently labelled BMP-2/7 and BMP-2, we demonstrated that the CHA scaffold provided a long-term delivery of both molecules for at least 20 days. Finally, using a rat femoral defect model, we showed that an ultra-low dose (0.5 µg) of BMP-2/7 accelerated fracture healing and performed at a level comparable to 20-times higher BMP-2 dose. Our results indicate that the sustained delivery of BMP-2/7 via a CHA scaffold could bring us a step closer in the quest for the use of physiological growth factor doses in fracture healing. STATEMENT OF SIGNIFICANCE: • Incorporation of hydroxyapatite (HA) in a collagen scaffold dramatically improves bone morphogenic protein (BMP) sequestration via biophysical interactions with BMP, thereby providing more controlled BMP release compared with pristine collagen. • We then investigate the molecular mechanisms responsible for increased osteoinductive potential of a heterodimer BMP-2/7 with is clinically used counterpart, the BMP-2 homodimer. • The superior osteoinductive properties of BMP-2/7 are a consequence of its direct positive effect on progenitor cell homing at the implantation site, which consequently leads to upregulation of cartilage and bone related genes and biochemical markers. • An ultra-low dose of BMP-2/7 delivered via a collagen-HA (CHA) scaffold leads to accelerated healing of a critical femoral defect in rats while a 20-times higher BMP-2 dose was required to achieve comparable results.</p>}},
  author       = {{Liu, Yang and Puthia, Manoj and Sheehy, Eamon J and Ambite, Ines and Petrlova, Jitka and Prithviraj, Sujeethkumar and Oxborg, Maria Wimer and Sebastian, Sujeesh and Vater, Corina and Zwingenberger, Stefan and Struglics, André and Bourgine, Paul E and O'Brien, Fergal J and Raina, Deepak Bushan}},
  issn         = {{1878-7568}},
  keywords     = {{Rats; Animals; Durapatite/pharmacology; Collagen/pharmacology; Osteogenesis; Bone and Bones; Fracture Healing; Bone Substitutes/pharmacology; Bone Morphogenetic Protein 2/pharmacology; Bone Regeneration}},
  language     = {{eng}},
  pages        = {{164--181}},
  publisher    = {{Elsevier}},
  series       = {{Acta Biomaterialia}},
  title        = {{Sustained delivery of a heterodimer bone morphogenetic protein-2/7 via a collagen hydroxyapatite scaffold accelerates and improves critical femoral defect healing}},
  url          = {{http://dx.doi.org/10.1016/j.actbio.2023.03.028}},
  doi          = {{10.1016/j.actbio.2023.03.028}},
  volume       = {{162}},
  year         = {{2023}},
}