Systematic Review
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Orthop. Apr 18, 2019; 10(4): 176-191
Published online Apr 18, 2019. doi: 10.5312/wjo.v10.i4.176
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 M Sciubba, Timothy F Witham
Ethan Cottrill, A Karim Ahmed, Noah Lessing, Zachary Pennington, Wataru Ishida, Alexander Perdomo-Pantoja, Sheng-fu Lo, Christina Holmes, Nicholas Theodore, Daniel M Sciubba, Timothy F Witham, Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, MD 21287, United States
Elizabeth Howell, C Rory Goodwin, Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, United States
Author contributions: Cottrill E, Ahmed AK, Lessing N, Pennington Z, Howell E: Conception and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for intellectual content. Ishida W, Perdomo-Pantoja A, Lo SF, Holmes C, Goodwin CR, Theodore N, Sciubba DM: Conception and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, supervision. Witham TF: Conception and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, obtaining funding, supervision. All authors reviewed and approved the final manuscript as submitted.
Conflict-of-interest statement: Goodwin CR: Grants from NIH/NINDS K12 Physician Scientist Award, North Carolina Spine Society, and Burroughs Wellcome Funds; all outside the submitted work. Lo SF: Research support from Chordoma Foundation, Grant from AO Spine; all outside the submitted work. Sciubba DM: Consulting from Baxter, DePuy Synthes, Globus, K2M, Medical Device Business Services, Medtronic, NuVasive, and Stryker; Speaking/Teaching from Globus Medical, Medtronic, and DePuy Synthes; all outside the submitted work. Theodore N: Royalties from Globus Medical, Depuy Synthes; Stock in Globus Medical; Consulting from Globus Medical; Scientific Advisory Board from Globus Medical; Fellowship Support from AO North America; all outside the submitted work. Witham TF: Grants from Eli Lilly Company and the Gordon and Marilyn Macklin Foundation.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Ethan Cottrill, MSc, Research Scientist, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287, United States. ecottri1@jhmi.edu
Telephone: +1-410-9554424
Received: October 22, 2018
Peer-review started: October 23, 2018
First decision: November 15, 2018
Revised: January 3, 2019
Accepted: January 26, 2019
Article in press: January 26, 2019
Published online: April 18, 2019
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.

Keywords: Spinal fusion, Growth factor, Pseudoarthrosis, Systematic review

Core tip: This is the first study to systematically review all the published investigational growth factors utilized in preclinical animal models of spinal fusion. Among the identified growth factors, calcitonin, GDF-5, NELL-1, and P-15 resulted in fusion rates of 100% in some studies. In addition, six growth factors - AB204, angiopoietin 1, GDF-5, insulin, NELL-1, and peptide B2A - resulted in significantly enhanced fusion rates compared to autologous iliac crest bone graft, BMP-2, or other internal controls in some cases. Directly comparing the fusion efficacy and safety of these growth factors may inform the development of clinically translatable materials for spinal fusion.