Investigational growth factors utilized in animal models of spinal fusion: Systematic review

Ethan Cottrill, A. Karim Ahmed, Noah Lessing, Zachary Pennington, Wataru Ishida, Alexander Perdomo-Pantoja, Sheng-fu Lo, Elizabeth Howell, Christina Holmes, C. Rory Goodwin, Nicholas Theodore, Daniel Sciubba, Timothy F Witham

Research output: Contribution to journalReview article

Abstract

BACKGROUND Over 400000 Americans annually undergo spinal fusion surgeries, yet up to 40% of these procedures result in pseudoarthrosis even with iliac crest autograft, the current "gold standard" treatment. Tissue engineering has the potential to solve this problem via the creation of bone grafts involving bone-promoting growth factors (e.g., bone morphogenetic protein 2). A broad assessment of experimental growth factors is important to inform future work and clinical potential in this area. To date, however, no study has systematically reviewed the investigational growth factors utilized in preclinical animal models of spinal fusion. AIM To review all published studies assessing investigational growth factors for spinal fusion in animal models and identify promising agents for translation. METHODS We conducted a systematic review of the literature using PubMed, Embase, Cochrane Library, and Web of Science databases with searches run on May 29th, 2018. The search query was designed to include all non-human, preclinical animal models of spinal fusion reported in the literature without a timespan limit. Extracted data for each model included surgical approach, level of fusion, animal species and breed, animal age and sex, and any other relevant characteristics. The dosages/sizes of all implant materials, spinal fusion rates, and follow-up time points were recorded. The data were analyzed and the results reported in tables and text. PRISMA guidelines were followed for this systematic review. RESULTS Twenty-six articles were included in this study, comprising 14 experimental growth factors: AB204 (n = 1); angiopoietin 1 (n = 1); calcitonin (n = 3); erythropoietin (n = 1); basic fibroblast growth factor (n = 1); growth differentiation factor 5 (n = 4), combined insulin-like growth factor 1 + transforming growth factor beta (n = 4); insulin (n = 1); NELL-1 (n = 5); noggin (n = 1); P-15 (n = 1); peptide B2A (n = 2); and secreted phosphoprotein 24 (n = 1). The fusion rates of the current gold standard treatment (autologous iliac crest bone graft, ICBG) and the leading clinically used growth factor (BMP-2) ranged widely in the included studies, from 0-100% for ICBG and from 13%-100% for BMP-2. Among the identified growth factors, calcitonin, GDF-5, NELL-1, and P- 15 resulted in fusion rates of 100% in some cases. In addition, six growth factors - AB204, angiopoietin 1, GDF-5, insulin, NELL-1, and peptide B2A - resulted in significantly enhanced fusion rates compared to ICBG, BMP-2, or other internal control in some studies. Large heterogeneity in animal species, fusion method, and experimental groups and time points was observed across the included studies, limiting the direct comparison of the growth factors identified herein. CONCLUSION Several promising investigational growth factors for spinal fusion have been identified herein; directly comparing the fusion efficacy and safety of these agents may inform clinical translation.

Original languageEnglish (US)
Pages (from-to)176-191
Number of pages16
JournalWorld Journal of Orthopaedics
Volume10
Issue number4
DOIs
StatePublished - Apr 1 2019

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Spinal Fusion
Intercellular Signaling Peptides and Proteins
Animal Models
Growth Differentiation Factor 5
Angiopoietin-1
Transplants
Bone and Bones
Calcitonin
Library Science
Insulin
Anatomic Models
Fibroblast Growth Factor 1
Bone Morphogenetic Protein 2
Peptides
Pseudarthrosis
Bone Development
Autografts
Somatomedins
Fibroblast Growth Factor 2
Tissue Engineering

Keywords

  • Growth factor
  • Pseudoarthrosis
  • Spinal fusion
  • Systematic review

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine

Cite this

Investigational growth factors utilized in animal models of spinal fusion : Systematic review. / Cottrill, Ethan; Ahmed, A. Karim; Lessing, Noah; Pennington, Zachary; Ishida, Wataru; Perdomo-Pantoja, Alexander; Lo, Sheng-fu; Howell, Elizabeth; Holmes, Christina; Rory Goodwin, C.; Theodore, Nicholas; Sciubba, Daniel; Witham, Timothy F.

In: World Journal of Orthopaedics, Vol. 10, No. 4, 01.04.2019, p. 176-191.

Research output: Contribution to journalReview article

Cottrill, E, Ahmed, AK, Lessing, N, Pennington, Z, Ishida, W, Perdomo-Pantoja, A, Lo, S, Howell, E, Holmes, C, Rory Goodwin, C, Theodore, N, Sciubba, D & Witham, TF 2019, 'Investigational growth factors utilized in animal models of spinal fusion: Systematic review', World Journal of Orthopaedics, vol. 10, no. 4, pp. 176-191. https://doi.org/10.5312/wjo.v10.i4.176
Cottrill E, Ahmed AK, Lessing N, Pennington Z, Ishida W, Perdomo-Pantoja A et al. Investigational growth factors utilized in animal models of spinal fusion: Systematic review. World Journal of Orthopaedics. 2019 Apr 1;10(4):176-191. https://doi.org/10.5312/wjo.v10.i4.176
Cottrill, Ethan ; Ahmed, A. Karim ; Lessing, Noah ; Pennington, Zachary ; Ishida, Wataru ; Perdomo-Pantoja, Alexander ; Lo, Sheng-fu ; Howell, Elizabeth ; Holmes, Christina ; Rory Goodwin, C. ; Theodore, Nicholas ; Sciubba, Daniel ; Witham, Timothy F. / Investigational growth factors utilized in animal models of spinal fusion : Systematic review. In: World Journal of Orthopaedics. 2019 ; Vol. 10, No. 4. pp. 176-191.
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abstract = "BACKGROUND Over 400000 Americans annually undergo spinal fusion surgeries, yet up to 40{\%} of these procedures result in pseudoarthrosis even with iliac crest autograft, the current {"}gold standard{"} treatment. Tissue engineering has the potential to solve this problem via the creation of bone grafts involving bone-promoting growth factors (e.g., bone morphogenetic protein 2). A broad assessment of experimental growth factors is important to inform future work and clinical potential in this area. To date, however, no study has systematically reviewed the investigational growth factors utilized in preclinical animal models of spinal fusion. AIM To review all published studies assessing investigational growth factors for spinal fusion in animal models and identify promising agents for translation. METHODS We conducted a systematic review of the literature using PubMed, Embase, Cochrane Library, and Web of Science databases with searches run on May 29th, 2018. The search query was designed to include all non-human, preclinical animal models of spinal fusion reported in the literature without a timespan limit. Extracted data for each model included surgical approach, level of fusion, animal species and breed, animal age and sex, and any other relevant characteristics. The dosages/sizes of all implant materials, spinal fusion rates, and follow-up time points were recorded. The data were analyzed and the results reported in tables and text. PRISMA guidelines were followed for this systematic review. RESULTS Twenty-six articles were included in this study, comprising 14 experimental growth factors: AB204 (n = 1); angiopoietin 1 (n = 1); calcitonin (n = 3); erythropoietin (n = 1); basic fibroblast growth factor (n = 1); growth differentiation factor 5 (n = 4), combined insulin-like growth factor 1 + transforming growth factor beta (n = 4); insulin (n = 1); NELL-1 (n = 5); noggin (n = 1); P-15 (n = 1); peptide B2A (n = 2); and secreted phosphoprotein 24 (n = 1). The fusion rates of the current gold standard treatment (autologous iliac crest bone graft, ICBG) and the leading clinically used growth factor (BMP-2) ranged widely in the included studies, from 0-100{\%} for ICBG and from 13{\%}-100{\%} for BMP-2. Among the identified growth factors, calcitonin, GDF-5, NELL-1, and P- 15 resulted in fusion rates of 100{\%} in some cases. In addition, six growth factors - AB204, angiopoietin 1, GDF-5, insulin, NELL-1, and peptide B2A - resulted in significantly enhanced fusion rates compared to ICBG, BMP-2, or other internal control in some studies. Large heterogeneity in animal species, fusion method, and experimental groups and time points was observed across the included studies, limiting the direct comparison of the growth factors identified herein. CONCLUSION Several promising investigational growth factors for spinal fusion have been identified herein; directly comparing the fusion efficacy and safety of these agents may inform clinical translation.",
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author = "Ethan Cottrill and Ahmed, {A. Karim} and Noah Lessing and Zachary Pennington and Wataru Ishida and Alexander Perdomo-Pantoja and Sheng-fu Lo and Elizabeth Howell and Christina Holmes and {Rory Goodwin}, C. and Nicholas Theodore and Daniel Sciubba and Witham, {Timothy F}",
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language = "English (US)",
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TY - JOUR

T1 - Investigational growth factors utilized in animal models of spinal fusion

T2 - Systematic review

AU - Cottrill, Ethan

AU - Ahmed, A. Karim

AU - Lessing, Noah

AU - Pennington, Zachary

AU - Ishida, Wataru

AU - Perdomo-Pantoja, Alexander

AU - Lo, Sheng-fu

AU - Howell, Elizabeth

AU - Holmes, Christina

AU - Rory Goodwin, C.

AU - Theodore, Nicholas

AU - Sciubba, Daniel

AU - Witham, Timothy F

PY - 2019/4/1

Y1 - 2019/4/1

N2 - BACKGROUND Over 400000 Americans annually undergo spinal fusion surgeries, yet up to 40% of these procedures result in pseudoarthrosis even with iliac crest autograft, the current "gold standard" treatment. Tissue engineering has the potential to solve this problem via the creation of bone grafts involving bone-promoting growth factors (e.g., bone morphogenetic protein 2). A broad assessment of experimental growth factors is important to inform future work and clinical potential in this area. To date, however, no study has systematically reviewed the investigational growth factors utilized in preclinical animal models of spinal fusion. AIM To review all published studies assessing investigational growth factors for spinal fusion in animal models and identify promising agents for translation. METHODS We conducted a systematic review of the literature using PubMed, Embase, Cochrane Library, and Web of Science databases with searches run on May 29th, 2018. The search query was designed to include all non-human, preclinical animal models of spinal fusion reported in the literature without a timespan limit. Extracted data for each model included surgical approach, level of fusion, animal species and breed, animal age and sex, and any other relevant characteristics. The dosages/sizes of all implant materials, spinal fusion rates, and follow-up time points were recorded. The data were analyzed and the results reported in tables and text. PRISMA guidelines were followed for this systematic review. RESULTS Twenty-six articles were included in this study, comprising 14 experimental growth factors: AB204 (n = 1); angiopoietin 1 (n = 1); calcitonin (n = 3); erythropoietin (n = 1); basic fibroblast growth factor (n = 1); growth differentiation factor 5 (n = 4), combined insulin-like growth factor 1 + transforming growth factor beta (n = 4); insulin (n = 1); NELL-1 (n = 5); noggin (n = 1); P-15 (n = 1); peptide B2A (n = 2); and secreted phosphoprotein 24 (n = 1). The fusion rates of the current gold standard treatment (autologous iliac crest bone graft, ICBG) and the leading clinically used growth factor (BMP-2) ranged widely in the included studies, from 0-100% for ICBG and from 13%-100% for BMP-2. Among the identified growth factors, calcitonin, GDF-5, NELL-1, and P- 15 resulted in fusion rates of 100% in some cases. In addition, six growth factors - AB204, angiopoietin 1, GDF-5, insulin, NELL-1, and peptide B2A - resulted in significantly enhanced fusion rates compared to ICBG, BMP-2, or other internal control in some studies. Large heterogeneity in animal species, fusion method, and experimental groups and time points was observed across the included studies, limiting the direct comparison of the growth factors identified herein. CONCLUSION Several promising investigational growth factors for spinal fusion have been identified herein; directly comparing the fusion efficacy and safety of these agents may inform clinical translation.

AB - BACKGROUND Over 400000 Americans annually undergo spinal fusion surgeries, yet up to 40% of these procedures result in pseudoarthrosis even with iliac crest autograft, the current "gold standard" treatment. Tissue engineering has the potential to solve this problem via the creation of bone grafts involving bone-promoting growth factors (e.g., bone morphogenetic protein 2). A broad assessment of experimental growth factors is important to inform future work and clinical potential in this area. To date, however, no study has systematically reviewed the investigational growth factors utilized in preclinical animal models of spinal fusion. AIM To review all published studies assessing investigational growth factors for spinal fusion in animal models and identify promising agents for translation. METHODS We conducted a systematic review of the literature using PubMed, Embase, Cochrane Library, and Web of Science databases with searches run on May 29th, 2018. The search query was designed to include all non-human, preclinical animal models of spinal fusion reported in the literature without a timespan limit. Extracted data for each model included surgical approach, level of fusion, animal species and breed, animal age and sex, and any other relevant characteristics. The dosages/sizes of all implant materials, spinal fusion rates, and follow-up time points were recorded. The data were analyzed and the results reported in tables and text. PRISMA guidelines were followed for this systematic review. RESULTS Twenty-six articles were included in this study, comprising 14 experimental growth factors: AB204 (n = 1); angiopoietin 1 (n = 1); calcitonin (n = 3); erythropoietin (n = 1); basic fibroblast growth factor (n = 1); growth differentiation factor 5 (n = 4), combined insulin-like growth factor 1 + transforming growth factor beta (n = 4); insulin (n = 1); NELL-1 (n = 5); noggin (n = 1); P-15 (n = 1); peptide B2A (n = 2); and secreted phosphoprotein 24 (n = 1). The fusion rates of the current gold standard treatment (autologous iliac crest bone graft, ICBG) and the leading clinically used growth factor (BMP-2) ranged widely in the included studies, from 0-100% for ICBG and from 13%-100% for BMP-2. Among the identified growth factors, calcitonin, GDF-5, NELL-1, and P- 15 resulted in fusion rates of 100% in some cases. In addition, six growth factors - AB204, angiopoietin 1, GDF-5, insulin, NELL-1, and peptide B2A - resulted in significantly enhanced fusion rates compared to ICBG, BMP-2, or other internal control in some studies. Large heterogeneity in animal species, fusion method, and experimental groups and time points was observed across the included studies, limiting the direct comparison of the growth factors identified herein. CONCLUSION Several promising investigational growth factors for spinal fusion have been identified herein; directly comparing the fusion efficacy and safety of these agents may inform clinical translation.

KW - Growth factor

KW - Pseudoarthrosis

KW - Spinal fusion

KW - Systematic review

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