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

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.

Novel, standardized pre-clinical surgical animal model to investigate the cellular and molecular mechanisms of ischemic flap healing

“…Alternatively, the PVA implants may be preloaded or continuously injected with a control vehicle or an experimental treatment solution to evaluate its impact on the migratory properties of different wound-bed cell populations, rate of granulation tissue (GT) formation and its health (thickness, vascularity), lymphangiogensis as well as deposition of extracellular matrix (ECM) and collagen bers (72)(73)(74)(75).…”

Current and Future Perspectives on Skin Tissue Engineering: Key Features of Biomedical Research, Translational Assessment, and Clinical Application

“…When exposed to S1P in vitro, these cells preferentially adopt anti‐inflammatory phenotypes and display a reduced secretion of proinflammatory cytokines if stimulated . Lim et al used S1P in combination with the antifungal agent ciclopirox olamine, which also displays proangiogenic activity . The group found that injection of the two agents into a polyvinyl alcohol sponge implanted in diabetic fatty rats supported endothelial migration and the formation of functional vessels.…”

Local pharmacological induction of angiogenesis: Drugs for cells and cells as drugs

“…However, in context with mesenchymal cells and unwounded or wounded tissue it became clear that angiogenic HIF1-α effects of PH inhibitors, even as so-called dirty tool, prevail. Shortly after the publication by Clement, and the mesenchymal endothelial crosstalk leading to angiogenesis was later demonstrated in greater detail in microfluidics systems [210,212] and diabetic wounds in experimental animal models [213,214]. The change viewpoints on PH inhibitors over time in the literature over time shows the importance of considering and implementing cellular cross-talk in angiogenic assays in vitro, as ECs are not the greatest producers of angiogenic factors, but rather the recipients of signals through them.…”