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Lim NS, Sham A, Chee SM, et al. Combination of ciclopirox olamine and sphingosine-1-phosphate as granulation enhancer in diabetic wounds. Wound Repair Regen. 2016;24(5):795-809doi: 10.1111/wrr.12463.
Lim, N. S., Sham, A., Chee, S. M., Chan, C., & Raghunath, M. (2016). Combination of ciclopirox olamine and sphingosine-1-phosphate as granulation enhancer in diabetic wounds. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society, 24(5), 795-809. https://doi.org/10.1111/wrr.12463
Lim, Natalie Sheng Jie, et al. "Combination of ciclopirox olamine and sphingosine-1-phosphate as granulation enhancer in diabetic wounds." Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society vol. 24,5 (2016): 795-809. doi: https://doi.org/10.1111/wrr.12463
Lim NS, Sham A, Chee SM, Chan C, Raghunath M. Combination of ciclopirox olamine and sphingosine-1-phosphate as granulation enhancer in diabetic wounds. Wound Repair Regen. 2016 Sep;24(5):795-809. doi: 10.1111/wrr.12463. Epub 2016 Aug 09. PMID: 27402256.
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Wound Repair Regen. 2016 Sep;24(5):795-809. doi: 10.1111/wrr.12463. Epub 2016 Aug 09.

Combination of ciclopirox olamine and sphingosine-1-phosphate as granulation enhancer in diabetic wounds.

Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society

Natalie Sheng Jie Lim, Adeline Sham, Stella Min Ling Chee, Casey Chan, Michael Raghunath

Affiliations

  1. Institute of Medical Biology, Biomedical Research Council, Agency for Science, Technology and Research, (A*STAR).
  2. Department of Biomedical Engineering, National University of Singapore.
  3. NUS Tissue Engineering Programme, Life Sciences Institute, National University of Singapore.
  4. Department of Orthopedic Surgery, Yong Loo Ling School of Medicine, National University of Singapore, Singapore.
  5. Institute of Medical Biology, Biomedical Research Council, Agency for Science, Technology and Research, (A*STAR). [email protected].
  6. Department of Biomedical Engineering, National University of Singapore. [email protected].
  7. NUS Tissue Engineering Programme, Life Sciences Institute, National University of Singapore. [email protected].
  8. Department of Biochemistry, Yong Loo Ling School of Medicine, National University of Singapore. [email protected].

PMID: 27402256 DOI: 10.1111/wrr.12463

Abstract

Granulation tissue formation requires a robust angiogenic response. As granulation tissue develops, collagen fibers are deposited and compacted. Forces generated in the wake of this process drive wound contraction to reduce the wound area. In diabetics, both angiogenesis and wound contraction are diminished leading to impaired wound healing. To emulate this pathology and to address it pharmacologically, we developed a wound healing model in the diabetic Zucker fatty rat and tested a topical proangiogenic strategy combining antifungal agent ciclopirox olamine (CPX) and lysophospholipid sphingosine-1-phosphate (S1P) to promote diabetic wound closure. In vitro, we demonstrated that CPX + S1P up-regulates a crucial driver of angiogenesis, hypoxia-inducible factor-1, in endothelial cells. Injection of CPX + S1P into subcutaneously implanted sponges in experimental rats showed, in an additive manner, a fivefold increased endothelial infiltration and lectin-perfused vessel length. We developed a splinted diabetic rodent model to achieve low wound contraction rates that are characteristic for the healing mode of diabetic ulcers in humans. We discovered specific dorsal sites that allowed for incremental full-thickness excisional wound depths from 1 mm (superficial) to 3 mm (deep). This enabled us to bring down wound contraction from 51% in superficial wounds to 8% in deep wounds. While the effects of topical gel treatment of CPX + S1P were masked by the rodent-characteristic dominant contraction in superficial wounds, they became clearly evident in deep diabetic wounds. Here, a fivefold increase of functional large vessels resulted in accelerated granulation tissue formulation, accompanied by a 40% increase of compacted thick collagen fibers. This was associated with substantially reduced matrix metalloproteinase-3 and -13 expression. These findings translated into a fivefold increase in granulation-driven contraction, promoting diabetic wound closure. With CPX and S1P analogues already in clinical use, their combination presents itself as an attractive proangiogenic treatment to be repurposed for diabetic wound healing.

© 2016 by the Wound Healing Society.

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