Clinical and histopathological effects of topical pentoxifylline on autonomisation processes in rat dorsal randomised skin flaps

Authors

  • Melike Zeynep Kuşçu Department of Plastic, Reconstructive and Aesthetic Surgery, Süleyman Demirel University Faculty of Medicine, Isparta, Türkiye
  • Selman Hakkı Altuntas Department of Plastic, Reconstructive and Aesthetic Surgery, Süleyman Demirel University Faculty of Medicine, Isparta, Türkiye
  • Özlem Özmen Department of Pathology, Burdur Mehmet Akif Ersoy University Faculty of Veterinary Medicine, Burdur, Türkiye
  • Simge Garlı Animal Experiments Production and Experimental Research Laboratory, Burdur Mehmet Akif Ersoy University Faculty of Veterinary Medicine, Burdur, Türkiye

DOI:

https://doi.org/10.2340/jphs.v61.45582

Keywords:

Flap autonomisation, flap viability, neoangiogenesis, topical pentoxifylline

Abstract

Background: Staged pedicled skin flaps that require pedicle division are frequently employed in reconstructive surgery, rely on their pedicle for vascular supply following transfer until neovascularisation occurs at the recipient site, a phenomenon referred to as autonomisation (pedicle-independent flap viability following neovascularisation). This study sought to investigate the application of topical pentoxifylline to expedite the autonomisation process.

Methods: Caudal-based skin flaps were surgically created in the dorsal region of 60 Wistar rats. On the fifth day, the bases of the flaps were surgically cut, and the flaps were subsequently monitored for an additional 7 days. The rats were divided into three groups: (1) Control group (Vaseline for 5 + 7 = 12 days), (2) Experimental-1 group (topical pentoxifylline for 5 days + vaseline for 7 days), and (3) Experimental-2 group (topical pentoxifylline for 5 + 7 = 12 days). Flap viability was assessed both macroscopically and microangiographically, and histopathological examinations were conducted.

Results: On day 12, the viable flap areas were 40.7% in the control group, 95.5% in experimental-1 group, and 100.0% in experimental-2 group (p < 0.05). Microangiography was conducted on day 5 and 12, and both experimental groups exhibited markedly greater vascularisation compared to the control group. Histopathological and immunohistochemical analyses revealed that pentoxifylline significantly enhanced angiogenesis, new vessel formation, and epithelisation, while mitigating early-stage inflammation, edema, and late-stage fibrosis (p < 0.05).

Conclusion: The application of topical pentoxifylline significantly promoted angiogenesis, thereby expediting the autonomisation of rat dorsal randomised skin flaps. Consequently, its use in reconstructive surgery may be considered, as it has the potential to reduce reliance on the pedicle, minimise complications, and enhance patient outcomes.

Downloads

Download data is not yet available.

References

Pederson WC, Lister GD. Local and regional flap coverage of the hand. In: Wolfe SW, editor. Green’s operative hand surgery. Philadelphia, PA: Elsevier Churchill; 2011. p. 1648–1713.

Pang CY, Neligan PC. Flap pathophysiology and pharmacology. In: Gurtner GC, Neligan PC, editors. Plastic surgery e-book. Volume I. Oxford: Elsevier Health Sciences; 2017. p. 573–586.

Pang CY, Forrest CR, Morris SF. Pharmacological augmentation of skin flap viability: a hypothesis to mimic the surgical delay phenomenon or a wishful thought. Ann Plast Surg. 1989;22(4):293–306.

https://doi.org/10.1097/00000637-198904000-00003 DOI: https://doi.org/10.1097/00000637-198904000-00003

Ward A, Clissold SP. Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs. 1987;34(1):50–97.

https://doi.org/10.2165/00003495-198734010-00003 DOI: https://doi.org/10.2165/00003495-198734010-00003

Angelkort B, Maurin N, Boateng K. Influence of pentoxifylline on erythrocyte deformability in peripheral occlusive arterial disease. Curr Med Res Opin. 1979;6(4):255–258.

https://doi.org/10.1185/03007997909109432 DOI: https://doi.org/10.1185/03007997909109432

Zhang M, Xu YJ, Mengi SA, et al. Therapeutic potentials of pentoxifylline for treatment of cardiovascular diseases. Exp Clin Cardiol. 2004;9(2):103–111.

Ciuffetti G, Mercuri M, Ott C, et al. Use of pentoxifylline as an inhibitor of free radical generation in peripheral vascular disease. Results of a double-blind placebo-controlled study. Eur J Clin Pharmacol. 1991;41(6):511–515.

https://doi.org/10.1007/BF00314976 DOI: https://doi.org/10.1007/BF00314976

Aviado DM, Dettelbach HR. Pharmacology of pentoxifylline, a hemorheologic agent for the treatment of intermittent claudication. Angiology. 1984;35(7):407–417.

https://doi.org/10.1177/000331978403500703 DOI: https://doi.org/10.1177/000331978403500703

Liang X, Wang Y, Zhao C, et al. Systematic review the efficacy and safety of cilostazol, pentoxifylline, beraprost in the treatment of intermittent claudication: a network meta-analysis. PLoS One. 2022;17(11):e0275392.

https://doi.org/10.1371/journal.pone.0275392 DOI: https://doi.org/10.1371/journal.pone.0275392

Roth AG, Briggs PC, Jones EW, et al. Augmentation of skin flap survival by parenteral pentoxifylline. Br J Plast Surg. 1988;41(5):515–520.

https://doi.org/10.1016/0007-1226(88)90010-0 DOI: https://doi.org/10.1016/0007-1226(88)90010-0

Takayanagi S, Ogawa Y. Effects of Pentoxifylline on flap survival. Plast Reconstr Surg. 1980;65(6):763–767.

https://doi.org/10.1097/00006534-198006000-00008 DOI: https://doi.org/10.1097/00006534-198006000-00008

Topalan M, Arıncı A, Erer M, et al. The effect of parenteral pentoxifylline therapy on skin flap survival. Eur J Plast Surg. 1993;16:33–35.

https://doi.org/10.1007/BF00192704 DOI: https://doi.org/10.1007/BF00192704

Najafi E, Ahmadi M, Mohammadi M, et al. Topical pentoxifylline for pressure ulcer treatment: a randomised, double-blind, placebo-controlled clinical trial. J Wound Care. 2018;27(8):495–502.

https://doi.org/10.12968/jowc.2018.27.8.495 DOI: https://doi.org/10.12968/jowc.2018.27.8.495

Mehrabani M, Najafi M, Kamarul T, et al. Deferoxamine preconditioning to restore impaired HIF-1α-mediated angiogenic mechanisms in adipose-derived stem cells from STZ-induced type 1 diabetic rats. Cell Prolif. 2015;48(5):532–549.

https://doi.org/10.1111/cpr.12209 DOI: https://doi.org/10.1111/cpr.12209

Payette JR, Kohlenberg E, Leonardi L, et al. Assessment of skin flaps using optically based methods for measuring blood flow and oxygenation. Plast Reconstr Surg. 2005;115(2):539–546.

https://doi.org/10.1097/01.PRS.0000148415.54546.CA DOI: https://doi.org/10.1097/01.PRS.0000148415.54546.CA

McFarlane RM, Deyoung G, Henry RA. The design of a pedicle flap in the rat to study necrosis and its prevention. Plast Reconstr Surg. 1965;35:177–182.

https://doi.org/10.1097/00006534-196502000-00007 DOI: https://doi.org/10.1097/00006534-196502000-00007

Ordman LJ, Gillman T. Studies in the healing of cutaneous wounds. 3. A critical comparison in the pig of the healing of surgical incisions closed with sutures or adhesive tape based on tensile strength and clinical and histological criteria. Arch Surg. 1966;93(6):911–928.

https://doi.org/10.1001/archsurg.1966.01330060055003 DOI: https://doi.org/10.1001/archsurg.1966.01330060055003

Velander E. Vascular changes in tubed pedicles. An animal experimental study. Acta Chir Scand Suppl. 1964;322(Suppl.):1–142.

Yucel B, Coruh A, Deniz K. Salvaging the zone of stasis in burns by Pentoxifylline: an experimental study in rats. J Burn Care Res. 2019;40(2):211–219.

https://doi.org/10.1093/jbcr/irz005 DOI: https://doi.org/10.1093/jbcr/irz005

Lancien U, Charbonnier B, Weiss P, et al. Rat perforator and skin vessels vascular mapping: an original anatomical study about 140 vessels and literature review. J Surg Res. 2023;288:298–308.

https://doi.org/10.1016/j.jss.2023.03.015 DOI: https://doi.org/10.1016/j.jss.2023.03.015

Abdel-Salam OM, Baiuomy AR, El-Shenawy SM, et al. The anti-inflammatory effects of the phosphodiesterase inhibitor pentoxifylline in the rat. Pharmacol Res. 2003;47(4):331–340.

https://doi.org/10.1016/S1043-6618(03)00002-1 DOI: https://doi.org/10.1016/S1043-6618(03)00002-1

Marques LJ, Zheng L, Poulakis N, et al. Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages. Am J Respir Crit Care Med. 1999;159(2):508–511.

https://doi.org/10.1164/ajrccm.159.2.9804085 DOI: https://doi.org/10.1164/ajrccm.159.2.9804085

Pedretti S, Rena CL, Orellano LAA, et al. Benefits of pentoxifylline for skin flap tissue repair in rats. Acta Cir Bras. 2020;35(11):e301105.

https://doi.org/10.1590/acb351105 DOI: https://doi.org/10.1590/acb351105

Seo MH, Myoung H, Lee JH, et al. Effects of pentoxifylline and tocopherol on an osteoradionecrosis animal model. J Craniomaxillofac Surg. 2020;48(7):621–631.

https://doi.org/10.1016/j.jcms.2020.02.008 DOI: https://doi.org/10.1016/j.jcms.2020.02.008

Fang CC, Lai MN, Chien CT, et al. Effects of pentoxifylline on peritoneal fibroblasts and silica-induced peritoneal fibrosis. Perit Dial Int. 2003;23(3):228–236.

https://doi.org/10.1177/089686080302300303 DOI: https://doi.org/10.1177/089686080302300303

Lin SL, Chen RH, Chen YM, et al. Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor. J Am Soc Nephrol. 2005;16(9):2702–2713.

https://doi.org/10.1681/ASN.2005040435 DOI: https://doi.org/10.1681/ASN.2005040435

Paulis G, Barletta D, Turchi P, et al. Efficacy and safety evaluation of pentoxifylline associated with other antioxidants in medical treatment of Peyronie’s disease: a case-control study. Res Rep Urol. 2016;8:1–10.

https://doi.org/10.2147/RRU.S97194 DOI: https://doi.org/10.2147/RRU.S97194

Bayramiçli M. Laboratuar sıçanının anatomisi. Ameliyat. Bayramiçli M. Deneysel mikrocerrahi. Temel Araştırma, Doku ve Organ Nakil Modelleri Argos iletişim Hizmetleri. 2005;119–184:75–98.

Scherer-Pietramaggiori SS, Pietramaggiori G, Orgill DP. Skin graft. In: Gurtner GC, Neligan PC, editors. Plastic surgery e-book. Volume I. Oxford: Elsevier Health Sciences; 2017. p. 573–586.

Wang W, Lu KJ, Yu CH, et al. Nano-drug delivery systems in wound treatment and skin regeneration. J Nanobiotechnol. 2019;17(1):82.

https://doi.org/10.1186/s12951-019-0514-y DOI: https://doi.org/10.1186/s12951-019-0514-y

Published

2026-03-25

How to Cite

Kuşçu, M. Z., Altuntas, S. H., Özmen, Özlem, & Garlı, S. (2026). Clinical and histopathological effects of topical pentoxifylline on autonomisation processes in rat dorsal randomised skin flaps. Journal of Plastic Surgery and Hand Surgery, 61(1), 56–64. https://doi.org/10.2340/jphs.v61.45582

Issue

Section

Original Research Articles