The Effect of Topical Tacrolimus on Pedicled Flap Survival

Abstract

Purpose Our previous rodent study demonstrated significantly decreased full-thickness necrosis in pedicled dorsal skin flaps with topical tacrolimus as compared with petroleum jelly. The pathophysiology of tissue necrosis involves lymphatic congestion, followed by venous congestion and ultimately arterial insufficiency. Topical tacrolimus has been shown to increase growth of lymphatic collateral vessels and decrease lymphedema, potentially obviating one contributor to necrosis. The purpose of this study was to investigate the vascular and histological differences between these 2 groups to identify the etiology of our research findings. Methods A 3 × 10-cm cranially based dorsal skin flap was raised and reinset on 22 Sprague Dawley rats. They were randomized to receive 0.2 g of either topical petroleum jelly or topical 0.1% tacrolimus ointment daily to the flaps. The rats were killed 7 days postoperatively. Two blinded reviewers marked the total flap area as well as areas of viable tissue, reversible ischemia, and necrotic tissue. Full-thickness biopsies of each area were taken from 2 randomly chosen animals in each group. Paraffin-embedded tissue was sectioned to generate hematoxylin and eosin–stained slides. Representative images of each area of the flap were taken less than 40× magnification using light microscopy. Arteries, veins, and lymphatics in the dermal layer were quantified under blinded conditions by a trained pathologist and calculated per cross-sectional area using Fiji software. Results The average area of the dorsal flaps in the control and tacrolimus groups was 22.5 and 23.9 cm2, respectively. Total necrotic area was significantly lower in rats receiving topical tacrolimus as compared with controls (P = 0.015). In the control cohort, average total number of vessels was 12.5, 6, and 0, in the areas of viable tissue, reversible ischemia, and necrosis, respectively. In the tacrolimus cohort, average total number of vessels increased was 20, 11.5, and 5.4, in the areas of viable tissue, reversible ischemia, and necrosis, respectively. Conclusions On a histological level, topical tacrolimus is correlated with increased vascular growth in areas most susceptible for ischemic damage as compared with topical control. Future work is needed to investigate vascular biomarkers and increase the power of our study.

The Effect of Presurgical and Postsurgical Topical Tacrolimus on Pedicled Flap Survival in Rats

“…Our group has previously shown tacrolimus application after injury significantly decreased the total necrotic area compared with controls 3 . Upon further histological analysis, we also demonstrated topical tacrolimus increased arterial, venous, and lymphatic growth in areas that were most susceptible for ischemic damage 6 …”

“…3 Upon further histological analysis, we also demonstrated topical tacrolimus increased arterial, venous, and lymphatic growth in areas that were most susceptible for ischemic damage. 6 Although the regulation of angiogenic and lymphangiogenic factors involved with wound healing is complex, the pharmacokinetic effects of topical tacrolimus doses most likely are associated with lymphangiogenic mechanisms involved with T-cell inflammatory responses. This is supported by previous studies demonstrating antilymphangiogenic growth factors such as tumor growth factor β1 7 and interferon γ 8 exerting its effects even in very high prolymphangiogenic environments of vascular endothelial growth factor.…”