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
Processing time: 178 Days and 12.2 Hours
ARTICLE HIGHLIGHTS
Research background

Over 400000 Americans undergo spinal fusion surgeries each year, with the number increasing yearly alongside a growing and aging population. However, pseudoarthrosis, or failed fusion, rates are reported to be as high as 40% in primary spinal fusion surgery and up to 60% in revision cases, even when the "gold standard" treatment of grafting bone from the patient’s own iliac crest is used.

Research motivation

To date, no study has systematically reviewed the experimental growth factors investigated for spinal fusion in preclinical animal models. Considering the efficacy and widespread use of recombinant growth factors (i.e., rhBMP-2 and rhPTH) to optimize spinal fusion, a broad assessment of experimental growth factors is essential to inform future work and clinical potential in this area.

Research objectives

Systematically review all published translational animal models assessing investigational growth factors for spinal fusion and identify promising agents for translation.

Research methods

A systematic review of the literature using PubMed, Embase, Cochrane Library, and Web of Science databases was performed. Inclusion criteria were original studies involving the implantation/administration of one or more identifiable, quantifiable, experimental growth factors (i.e., not BMPs or PTH) in an animal model of spinal fusion in the English language. Exclusion criteria were studies that involved the implantation of (1) scaffolds without growth factors; (2) BMPs or PTH, (3) non-peptide-based agents, and (4) cells, platelet-rich plasma, or other processed blood products that could confound effects of the growth factors. PRISMA guidelines were followed for this systematic review.

Research results

The literature search identified 4806 total articles, from which 26 articles met the inclusion/exclusion criteria and were included in this review. Among the included studies, 14 experimental growth factors were identified: 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). 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.

Research conclusions

This is the first study to systematically review all the published investigational growth factors utilized in preclinical animal models of spinal fusion. Future studies aimed at directly comparing the most promising investigational growth factors identified herein - e.g., AB204, COMP-Ang-1, GDF-5, NELL-1, P-15, insulin, Peptide B2A, and others - in preclinical models may inform the development of efficacious and safe, clinically translatable materials for spinal fusion.

Research perspectives

The successful clinical translation of any factor intended to enhance spinal fusion will depend not only on its capacity to promote strong and reliable spinal fusion in humans, but also on its safety profile. Our study reveals that relatively few growth factors and delivery strategies in the overall setting of bone tissue engineering have been investigated in spinal fusion. We encourage future investigation of currently unexplored growth factors for spinal fusion, as well as continued advancements in growth factor delivery methods and scaffold materials, towards the development of efficacious and safe, clinically translatable materials for spinal fusion.