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
Research background

Numerous studies have emphasized the association of multiple risk factors, including alcohol consumption, glucocorticoids, trauma, autoimmune diseases, thrombophilia, genetic and metabolic components with secondary osteonecrosis (ON). ON of the femoral head (FH) is a debilitating disease that usually leads to osteoarthritis of the hip joint in young adults and up to now total hip replacement is predestinate in the long term.

Research motivation

Early diagnosis and management aims to suspend the process of joint destruction through enhancement of bone repair and bone renewal. In the early stages of ONFH there are surgical alternatives to restrain the progressive destruction of the subchondral bone such as core decompression, osteotomy, non-vascularized or vascularized bone grafting. This study extended the prospect of use growth and angiogenic factors for the process of repair at the necrotic trabeculae of the FH.

Research objectives

The main aim of this research project was to evaluate the treatment of ONFH with the use of vascular endothelial growth factor (VEGF).

Research methods

An experimental model of cryosurgically-induced ONFH in canines was used to assess the power of our hypothesis that VEGF could be a crucial therapeutic factor for bone tissue remodeling and reversal of osseous degradation during the treatment of ON. VEGF (2 different doses of 500 μg and 500 ng) was either injected in a single dose or administered continuously in the necrotic area with the use of an osmotic micropump, while in a control group 0.9% sodium chloride (NS) was injected in the necrotic area.

Research results

The untreated group had signs of ONFH, whereas the treatment groups with VEGF revealed reversal of the osteonecrosis, except the group treated with NS, that served as control. These findings demonstrate that the bone regeneration process in the osteonecrotic microenvironment could be affected by manipulation of VEGF levels.

Research conclusions

We demonstrated that the use of the VEGF affects in a positive and dose dependent manner the necrotic bone and induces the process of osseous regeneration. Since now it is well established by numerous studies that there are strong indications of a cellular and molecular pattern of angiogenic-osteogenic coupling. The restoration of bone vascularity is an absolute parameter in the process of osteoinduction, which is the target of any therapeutic agent against ONFH.

Research perspectives

In a reproducible experimental model of ONFH in mature beagles it was found that the treatment with VEGF leads to bone tissue remodeling and new bone formation at the osteonecrotic site and subsequently to reversal of ON. Besides that, the optimal delivery model of VEGF needs to be further studied. Utilizing a well-designed delivery system, like specific slow release scaffolds or gene delivery projects, may potentially lead to better bone regeneration and improve VEGFs therapeutic effect by stabilizing it against rapid degradation. Even if VEGF is sufficient to improve revascularization, recently scientists introduced the use of a combination of growth factors and manipulated progenitor cells to enhance bone repair and bone renewal. Although local VEGF administration is known to enhance new bone formation in ONFH in our study, future studies should further investigate, in a variety of experimental conditions, the role of VEGF as a key molecule and essential player for therapeutic strategies targeting bone reconstruction, so that an even transition to clinical trials may be achieved.