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Effects of CB-VEGF-A Injection in Rat Flap Models for Improved Survival

Lineaweaver, William C. M.D.; Zhang, Feng M.D., Ph.D.

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Plastic and Reconstructive Surgery: March 2014 - Volume 133 - Issue 3 - p 423e-424e
doi: 10.1097/01.prs.0000438450.63153.25
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Akimoto and coauthors recently published a study of vascular endothelial growth factor (VEGF) and flap survival in a rat model.1 Using a paired dorsal flap preparation, these investigators reported enhanced flap survival when VEGF combined with a Clostridium-derived collagen binding domain (CB-VEGF) was injected into flaps at the time of elevation. This improvement in flap survival was established relative to flaps injected with saline and unmodified VEGF, neither of which resulted in enhanced flap survival in these experiments. We wish to point out two problems with this study.

First, Akimoto et al. ignored a large body of previous work studying the effects of VEGF on flap survival (Table 1).2 At least 11 studies have documented increased survival of dorsal rat flaps with various routes of VEGF application, and none of these studies is mentioned in their article. At least 41 articles have been published examining the effects of VEGF in other rat flap models. Only four of these articles are cited by Akimoto et al., and these citations include only gene therapy experiments. The larger numbers of studies using locally injected VEGF are not noted. By ignoring this large body of work, the authors are giving their observations of CB-VEGF effects an unwarranted semblance of novelty.

Table 1
Table 1:
Rat Models Demonstrating Enhanced Flap Survival with VEGF Administration*

Second, neglect of previously published work deprived the authors of an opportunity to address an important problem with their own experimental findings. In this study, injection of unmodified VEGF had no positive effect on flap survival. This result is in direct contradiction to the many studies noted above in which VEGF has repeatedly been demonstrated to enhance survival in dorsal rat flap models. This disagreement with a large body of previously published work permits speculation that the CB-VEGF effect described in this experiment is simply the VEGF effect noted by many other investigators. The lack of effect in the authors’ VEGF group could reflect a problem in the preparation, maintenance, or administration of their VEGF.

The authors discuss the well-known concept of the short half-life of VEGF and postulate that there is a “sustained-release” effect created by CB-VEGF. They offer no evidence for this effect beyond the improved flap survival relative to VEGF in their own experiment. Given the context of previous work by other investigators, a simple explanation could conclude that their CB-VEGF demonstrated the well-described improvement of flap tissue survival noted in many models and their finding of no tissue survival improvement with simple VEGF was an anomaly. Their contention that their CB-VEGF findings represent an exceptional characteristic of this compound appears unwarranted.

Given the short half-life of VEGF, it is reasonable to investigate the possibilities of this growth factor acting through cascades of biologic activity.3 This conceptual framework suggests that future work could most productively be applied to understanding the interrelationships of VEGF rather than modifying the agent itself.


The authors have no financial interest to declare in relation to the content of this article.

William C. Lineaweaver, M.D.

JMS Burn and Reconstruction Center, Jackson, Miss.

Feng Zhang, M.D., Ph.D.

Division of Plastic Surgery, University of Mississippi Medical Center, Jackson, Miss.


1. Akimito M, Takeda A, Matsushita O, et al. Effects of CB-VEGF-A injection in rat flap models for improved survival. Plast Reconstr Surg. 2013;131:717–725
2. Fang T, Lineaweaver W, Chen M, Kisner C, Zhang F. Effects of vascular endothelial growth factor on survival of surgical flaps: A review of experimental studies. J Reconstr Microsurg. 2014;30:1–14
3. Zhang F, Lineaweaver W. Acute and sustained effects of vascular endothelial growth factor on survival of flaps and skin grafts. Ann Plast Surg. 2011;66:581–582


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