Effect of rhBMP-2 dose on bone formation/maturation in a rat critical-size calvarial defect model

Manuel Pelaez, Cristiano Susin, Jaebum Lee, Tiago Fiorini, Frederick C. Bisch, Douglas R. Dixon, James C. McPherson, Amanda N. Buxton, Ulf M E Wikesjö

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Background Application of recombinant human bone morphogenetic protein-2 (rhBMP-2) has been associated with significant adverse events in craniofacial settings, including swelling and seroma formation. Recent work has demonstrated an inverse relationship between bone formation/maturation and rhBMP-2 dose, frequency/severity of adverse events increasing with rising dose. Objective The objective of this study was to determine the most effective dose for rhBMP-2 soak-loaded onto an absorbable collagen sponge (ACS) carrier for bone formation/maturation using an established defect model. Methods One hundred sixty-eight outbred male Sprague-Dawley rats, age 11-13 weeks, weight 325-375 g randomized into seven groups of 24 subdivided into groups of eight, were used to provide radiographic and light microscopy observations of bone formation/maturation and aberrant healing events at 2, 4 and 8 weeks following application of rhBMP-2/ACS into critical-size, ø8-mm, through-through, calvarial osteotomy defects for a dose of 1.25, 2.5, 5.0, 10.0 and 20.0 μg rhBMP-2/defect, or serve as ACS or sham-surgery controls. Results rhBMP-2 dosages ≥2.5 μg/defect showed histological defect closure >90% within 2 weeks, and complete resolution within 4 weeks. Adverse healing events including swelling, excessive bone formation or seroma formation could not be determined with certainty in this defect model. Notably ACS control sites showed complete defect closure at the 8-week healing interval. Conclusions rhBMP-2/ACS accelerates local bone formation in the rat critical-size through-through calvarial defect model once reaching an osteoinductive dose threshold. This threshold may already be reached at a 1.25-/2.5-μg dose in this model. No further enhancement to bone formation/maturation may be observed adding rhBMP-2 above the 2.5-μg dose. The 1.25-20.0 μg dose range did not invoke appreciable aberrant healing events.

Original languageEnglish (US)
Pages (from-to)827-836
Number of pages10
JournalJournal of Clinical Periodontology
Volume41
Issue number8
DOIs
StatePublished - Aug 2014

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Osteogenesis
Porifera
Collagen
Seroma
recombinant human bone morphogenetic protein-2
Osteotomy
Sprague Dawley Rats
Microscopy
Light
Weights and Measures

Keywords

  • BMP-2
  • animal models
  • bone formation
  • bone maturation
  • calvarial bone
  • dose

ASJC Scopus subject areas

  • Periodontics

Cite this

Pelaez, M., Susin, C., Lee, J., Fiorini, T., Bisch, F. C., Dixon, D. R., ... Wikesjö, U. M. E. (2014). Effect of rhBMP-2 dose on bone formation/maturation in a rat critical-size calvarial defect model. Journal of Clinical Periodontology, 41(8), 827-836. https://doi.org/10.1111/jcpe.12270

Effect of rhBMP-2 dose on bone formation/maturation in a rat critical-size calvarial defect model. / Pelaez, Manuel; Susin, Cristiano; Lee, Jaebum; Fiorini, Tiago; Bisch, Frederick C.; Dixon, Douglas R.; McPherson, James C.; Buxton, Amanda N.; Wikesjö, Ulf M E.

In: Journal of Clinical Periodontology, Vol. 41, No. 8, 08.2014, p. 827-836.

Research output: Contribution to journalArticle

Pelaez, M, Susin, C, Lee, J, Fiorini, T, Bisch, FC, Dixon, DR, McPherson, JC, Buxton, AN & Wikesjö, UME 2014, 'Effect of rhBMP-2 dose on bone formation/maturation in a rat critical-size calvarial defect model', Journal of Clinical Periodontology, vol. 41, no. 8, pp. 827-836. https://doi.org/10.1111/jcpe.12270
Pelaez, Manuel ; Susin, Cristiano ; Lee, Jaebum ; Fiorini, Tiago ; Bisch, Frederick C. ; Dixon, Douglas R. ; McPherson, James C. ; Buxton, Amanda N. ; Wikesjö, Ulf M E. / Effect of rhBMP-2 dose on bone formation/maturation in a rat critical-size calvarial defect model. In: Journal of Clinical Periodontology. 2014 ; Vol. 41, No. 8. pp. 827-836.
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abstract = "Background Application of recombinant human bone morphogenetic protein-2 (rhBMP-2) has been associated with significant adverse events in craniofacial settings, including swelling and seroma formation. Recent work has demonstrated an inverse relationship between bone formation/maturation and rhBMP-2 dose, frequency/severity of adverse events increasing with rising dose. Objective The objective of this study was to determine the most effective dose for rhBMP-2 soak-loaded onto an absorbable collagen sponge (ACS) carrier for bone formation/maturation using an established defect model. Methods One hundred sixty-eight outbred male Sprague-Dawley rats, age 11-13 weeks, weight 325-375 g randomized into seven groups of 24 subdivided into groups of eight, were used to provide radiographic and light microscopy observations of bone formation/maturation and aberrant healing events at 2, 4 and 8 weeks following application of rhBMP-2/ACS into critical-size, {\o}8-mm, through-through, calvarial osteotomy defects for a dose of 1.25, 2.5, 5.0, 10.0 and 20.0 μg rhBMP-2/defect, or serve as ACS or sham-surgery controls. Results rhBMP-2 dosages ≥2.5 μg/defect showed histological defect closure >90{\%} within 2 weeks, and complete resolution within 4 weeks. Adverse healing events including swelling, excessive bone formation or seroma formation could not be determined with certainty in this defect model. Notably ACS control sites showed complete defect closure at the 8-week healing interval. Conclusions rhBMP-2/ACS accelerates local bone formation in the rat critical-size through-through calvarial defect model once reaching an osteoinductive dose threshold. This threshold may already be reached at a 1.25-/2.5-μg dose in this model. No further enhancement to bone formation/maturation may be observed adding rhBMP-2 above the 2.5-μg dose. The 1.25-20.0 μg dose range did not invoke appreciable aberrant healing events.",
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AU - Susin, Cristiano

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AU - Fiorini, Tiago

AU - Bisch, Frederick C.

AU - Dixon, Douglas R.

AU - McPherson, James C.

AU - Buxton, Amanda N.

AU - Wikesjö, Ulf M E

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N2 - Background Application of recombinant human bone morphogenetic protein-2 (rhBMP-2) has been associated with significant adverse events in craniofacial settings, including swelling and seroma formation. Recent work has demonstrated an inverse relationship between bone formation/maturation and rhBMP-2 dose, frequency/severity of adverse events increasing with rising dose. Objective The objective of this study was to determine the most effective dose for rhBMP-2 soak-loaded onto an absorbable collagen sponge (ACS) carrier for bone formation/maturation using an established defect model. Methods One hundred sixty-eight outbred male Sprague-Dawley rats, age 11-13 weeks, weight 325-375 g randomized into seven groups of 24 subdivided into groups of eight, were used to provide radiographic and light microscopy observations of bone formation/maturation and aberrant healing events at 2, 4 and 8 weeks following application of rhBMP-2/ACS into critical-size, ø8-mm, through-through, calvarial osteotomy defects for a dose of 1.25, 2.5, 5.0, 10.0 and 20.0 μg rhBMP-2/defect, or serve as ACS or sham-surgery controls. Results rhBMP-2 dosages ≥2.5 μg/defect showed histological defect closure >90% within 2 weeks, and complete resolution within 4 weeks. Adverse healing events including swelling, excessive bone formation or seroma formation could not be determined with certainty in this defect model. Notably ACS control sites showed complete defect closure at the 8-week healing interval. Conclusions rhBMP-2/ACS accelerates local bone formation in the rat critical-size through-through calvarial defect model once reaching an osteoinductive dose threshold. This threshold may already be reached at a 1.25-/2.5-μg dose in this model. No further enhancement to bone formation/maturation may be observed adding rhBMP-2 above the 2.5-μg dose. The 1.25-20.0 μg dose range did not invoke appreciable aberrant healing events.

AB - Background Application of recombinant human bone morphogenetic protein-2 (rhBMP-2) has been associated with significant adverse events in craniofacial settings, including swelling and seroma formation. Recent work has demonstrated an inverse relationship between bone formation/maturation and rhBMP-2 dose, frequency/severity of adverse events increasing with rising dose. Objective The objective of this study was to determine the most effective dose for rhBMP-2 soak-loaded onto an absorbable collagen sponge (ACS) carrier for bone formation/maturation using an established defect model. Methods One hundred sixty-eight outbred male Sprague-Dawley rats, age 11-13 weeks, weight 325-375 g randomized into seven groups of 24 subdivided into groups of eight, were used to provide radiographic and light microscopy observations of bone formation/maturation and aberrant healing events at 2, 4 and 8 weeks following application of rhBMP-2/ACS into critical-size, ø8-mm, through-through, calvarial osteotomy defects for a dose of 1.25, 2.5, 5.0, 10.0 and 20.0 μg rhBMP-2/defect, or serve as ACS or sham-surgery controls. Results rhBMP-2 dosages ≥2.5 μg/defect showed histological defect closure >90% within 2 weeks, and complete resolution within 4 weeks. Adverse healing events including swelling, excessive bone formation or seroma formation could not be determined with certainty in this defect model. Notably ACS control sites showed complete defect closure at the 8-week healing interval. Conclusions rhBMP-2/ACS accelerates local bone formation in the rat critical-size through-through calvarial defect model once reaching an osteoinductive dose threshold. This threshold may already be reached at a 1.25-/2.5-μg dose in this model. No further enhancement to bone formation/maturation may be observed adding rhBMP-2 above the 2.5-μg dose. The 1.25-20.0 μg dose range did not invoke appreciable aberrant healing events.

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