Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Orthop. Sep 18, 2018; 9(9): 120-129
Published online Sep 18, 2018. doi: 10.5312/wjo.v9.i9.120
Vascular endothelial growth factor for the treatment of femoral head osteonecrosis: An experimental study in canines
Zoe H Dailiana, Nikolaos Stefanou, Lubna Khaldi, Georgios Dimakopoulos, James R Bowers, Cristian Fink, James R Urbaniak
Zoe H Dailiana, Nikolaos Stefanou, Department of Orthopaedic Surgery, Faculty of Medicine, University of Thessalia, Larissa 41500, Greece
Zoe H Dailiana, James R Bowers, Cristian Fink, James R Urbaniak, Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710, United States
Lubna Khaldi, Department of Pathology, “Saint Savvas” Anti-Cancer Hospital, Athens 11522, Greece
Georgios Dimakopoulos, Medical Statistics, Epirus Science and Technology Park Campus of the University of Ioannina, Ioannina 45500, Greece
James R Bowers, Emerge Ortho, Independence Park, Durham, NC 27704, United States
Cristian Fink, Gelenkpunkt, Sports and Joint Surgery, Innsbruck 6020, Austria
Cristian Fink, Research Unit of Orthopedic Sports Medicine and Injury Prevention, Institute for Sports Medicine, Alpine Medicine and Health Tourism (ISAG), UMIT, Tirol 6060, Austria
Author contributions: Dailiana ZH participated in the inception and design of the study, the acquisition and the interpretation of the data, and wrote the manuscript; Stefanou N critically reviewed the findings and wrote the manuscript; Khaldi L performed the qualitative histological estimation, quantitative bone histomorphometry and the photography of sections, wrote the histological/histomorphometrical materials and methods and the histological figure legends; Dimakopoulos G performed the statistical analysis; Bowers JR and Fink C participated in the acquisition and interpretation of the data and helped draft the manuscript; Urbaniak JR participated in the inception and design of the study, critically reviewed the findings, and revised the manuscript.
Supported by Piedmont Orthopaedic Foundation, United States.
Institutional review board statement: The experimental study was approved from the Institutional Animal Care and Use Committee of Duke University.
Conflict-of-interest statement: We have no financial relationships to disclose.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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:
Correspondence to: Zoe H Dailiana, MD, PhD, Professor, Surgeon, Department of Orthopaedic Surgery, Faculty of Medicine, University of Thessalia, 3 Panepistimiou St., Larissa 41500, Greece.
Telephone: +30-24-13502722 Fax: +30-24-13501011
Received: March 29, 2018
Peer-review started: March 29, 2018
First decision: April 29, 2018
Revised: June 20, 2018
Accepted: June 26, 2018
Article in press: June 27, 2018
Published online: September 18, 2018

To evaluate the treatment of osteonecrosis of the femoral head (ONFH) with the use of vascular endothelial growth factor (VEGF).


In 30 mature beagles (6 groups of 5 beagles) ONFH was induced cryosurgically and one of the following solutions was administered locally in the femoral head (FH) in each group: Single injection of 500 μg VEGF (t-VEGFμ group); single injection of 500 ng VEGF (t-VEGFn group); continuous delivery of 500 μg VEGF through osmotic micropump (t-VEGFpump-μ group); continuous delivery of 500 ng VEGF through osmotic micropump (t-VEGFpump-n group); single injection of 0.9% sodium chloride (t-NS group), while one group that served as control group did not receive any local solution (No-t group). FHs were retrieved 12 wk postoperatively, underwent decalcification and hematoxylin/eosin and toluidine blue staining. In two canines per group, one half of FH was processed without decalcification and stained with modified Masson Trichrome. Histological sections were observed by light microscopy and measured with a semi-automatized bone histomorphometry system and Bone Volume/Total Volume (BV/TV), Marrow Volume/Total Volume (MaV/TV), and Trabecular Thickness (TbTh) were assessed. Standard and robust tests (Welch, Brown Forsythe) of analysis of variance along with multiple comparisons, were carried out among the categories.


The untreated (No-t) group had signs of osteonecrosis, whereas the VEGF groups revealed reversal of the osteonecrosis. Statistical analysis of the decalcified specimens revealed a significantly better BV/TV ratio and a higher TbTh between the VEGF treatment groups (except the t-VEGFn group) and the No-t group or the control t-NS group. Single dose 500 μgVEGF group had significantly better BV/TV ratio and higher TbTh when compared to the No-t group (50.45 ± 6.18 vs 29.50 ± 12.27, P = 0.002 and 151.44 ± 19.07 vs 107.77 ± 35.15, P = 0.161 respectively) and the control t-NS group (50.45 ± 6.18 vs 30.9 ± 6.67, P = 0.004 and 151.44 ± 19.07 vs 107.14 ± 35.71, P = 0.151 respectively). Similar differences were found for the prolonged VEGF delivery/pump groups of 500 μg and 500 ng. Analysis of the totality of specimens (decalcified/non-decalcified) enhanced the aforementioned differences and additionally revealed significant differences in the comparison of the TbTh.


In an experimental model of ONFH in canines it was found that local treatment with VEGF leads to bone tissue remodeling and new bone formation.

Keywords: Osteonecrosis, Vascular endothelial growth factor, Avascular necrosis, Femoral head, Osteogenesis, Animal model

Core tip: Osteonecrosis of the femoral head (ONFH) is a painful disorder which usually results in hip joint destruction. Although the pathogenic process is poorly understood, ON is the final condition that completes an already precarious microcirculation of the FH by traumatic and non-traumatic causes. Since vascular endothelial growth factor (VEGF) regulates numerous cellular events associated with angiogenesis and osteogenesis, we evaluated, in an experimental model of ONFH in canines if the local treatment with VEGF leads to bone tissue remodeling and new bone formation at the necrotic site, and subsequently to reversal of ON.