Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration

D. H R Kempen, Lichun Lu, Andras Heijink, Theresa E. Hefferan, Laura B. Creemers, Avudaiappan Maran, Michael J Yaszemski, W. J A Dhert

Research output: Contribution to journalArticle

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Abstract

Bone regeneration is a coordinated cascade of events regulated by several cytokines and growth factors. Angiogenic growth factors are predominantly expressed during the early phases for re-establishment of the vascularity, whereas osteogenic growth factors are continuously expressed during bone formation and remodeling. Since vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs) are key regulators of angiogenesis and osteogenesis during bone regeneration, the aim of this study was to investigate if their sequential release could enhance BMP-2-induced bone formation. A composite consisting of poly(lactic-co-glycolic acid) microspheres loaded with BMP-2 embedded in a poly(propylene) scaffold surrounded by a gelatin hydrogel loaded with VEGF was used for the sequential release of the growth factors. Empty composites or composites loaded with VEGF and/or BMP-2 were implanted ectopically and orthotopically in Sprague-Dawley rats (n = 9). Following implantation, the local release profiles were determined by measuring the activity of 125I-labeled growth factors using scintillation probes. After 8 weeks blood vessel and bone formation were analyzed using microangiography, μCT and histology. The scaffolds exhibited a large initial burst release of VEGF within the first 3 days and a sustained release of BMP-2 over the full 56-day implantation period. Although VEGF did not induce bone formation, it did increase the formation of the supportive vascular network (p = 0.03) in ectopic implants. In combination with local sustained BMP-2 release, VEGF significantly enhanced ectopic bone formation compared to BMP-2 alone (p = 0.008). In the orthotopic defects, no effect of VEGF on vascularisation was found, nor was bone formation higher by the combination of growth factors, compared to BMP-2 alone. This study demonstrates that a sequential angiogenic and osteogenic growth factor release may be beneficial for the enhancement of bone regeneration.

Original languageEnglish (US)
Pages (from-to)2816-2825
Number of pages10
JournalBiomaterials
Volume30
Issue number14
DOIs
StatePublished - May 2009

Fingerprint

Bone Morphogenetic Protein 2
Bone Regeneration
Osteogenesis
Vascular Endothelial Growth Factor A
Intercellular Signaling Peptides and Proteins
Bone
Proteins
Blood Vessels
Composite materials
Bone Morphogenetic Proteins
Bone Remodeling
Angiogenesis Inducing Agents
Hydrogel
Gelatin
Microspheres
Histology
Sprague Dawley Rats
Scaffolds (biology)
Blood vessels
Scintillation

Keywords

  • Bone morphogenetic protein-2
  • Bone regeneration
  • Local release
  • Vascular endothelial growth factor
  • Vessel formation

ASJC Scopus subject areas

  • Biophysics
  • Bioengineering
  • Mechanics of Materials
  • Biomaterials
  • Ceramics and Composites

Cite this

Kempen, D. H. R., Lu, L., Heijink, A., Hefferan, T. E., Creemers, L. B., Maran, A., ... Dhert, W. J. A. (2009). Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration. Biomaterials, 30(14), 2816-2825. https://doi.org/10.1016/j.biomaterials.2009.01.031

Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration. / Kempen, D. H R; Lu, Lichun; Heijink, Andras; Hefferan, Theresa E.; Creemers, Laura B.; Maran, Avudaiappan; Yaszemski, Michael J; Dhert, W. J A.

In: Biomaterials, Vol. 30, No. 14, 05.2009, p. 2816-2825.

Research output: Contribution to journalArticle

Kempen, DHR, Lu, L, Heijink, A, Hefferan, TE, Creemers, LB, Maran, A, Yaszemski, MJ & Dhert, WJA 2009, 'Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration', Biomaterials, vol. 30, no. 14, pp. 2816-2825. https://doi.org/10.1016/j.biomaterials.2009.01.031
Kempen, D. H R ; Lu, Lichun ; Heijink, Andras ; Hefferan, Theresa E. ; Creemers, Laura B. ; Maran, Avudaiappan ; Yaszemski, Michael J ; Dhert, W. J A. / Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration. In: Biomaterials. 2009 ; Vol. 30, No. 14. pp. 2816-2825.
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